Pyrimidinyl-propionic acid derivatives and their use as ppar agonists

ABSTRACT

The present invention disclosed compounds of Structural Formula (I), and enantiomer, racemic body, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein variable groups are as defined within, as well as methods for preparing such compounds. The compounds are useful as PPARγ agonist, through activating PPAR-RXR heterodimers that intereacts with specific DNA response elements within promoter regions of target gene, particularly in the treatment and prevention of polycystic kidney and cancer.

BACKGROUND OF THE INVENTION

Peroxisome proliferators-activated receptors (PPARs) are members of thenuclear hormone receptor superfamily. There are three PPAR subtypes,which are the products of distinct genes and are commonly designatedPPARα, PPARγ and PPARδ. Among them, PPARγ is the most extensivelystudied. Through heterodimerization with retinoid X receptors (RXRs),PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisomeproliferator response elements (PPREs), regulating the transcription ofgenes whose products are involved in lipid homeostasis, cell growth, anddifferentiation. Recent studies have shown that PPAR-γ is not onlycorrelated to diseases such as obesity, insulin resistance, diabetes,hypertension, artherosclerosis, inflammation, but also potential targetfor treatment of ADPKD and cancer.

Hereditary forms of polycystic kidney disease (PKD) in humans aretransmitted in either an autosomal recessive (ARPKD) or an autosomaldominant pattern (ADPKD), ADPKD, one of the most common, potentiallylethal single-gene disorders, is the leading form of inherited kidneydisorders. It is characterized by the accumulation of fluid-filled cystsin the cortex and medulla of bilateral kidneys and other organs likeliver, seminal vesicles, pancreas and arachnoid membrane, causingextrarenal abnormalities such as intracranial aneurysms anddolichoectasias, dilatation of the aortic root, dissection of thethoracic aorta, mitral valve prolapse and abdominal wall hernias. Itaffects about 1:500 to 1:1000 people in all ethnic groups worldwide. InChina, about 1,500,000 people have ADPKD, approximately 50% of peoplewith it develop renal failure at the age of 60.

Since the genes responsible for ADPKD have been cloned and genediagnosis, imaging detecting technologies have been developed quickly,prenatal/presymptomatic diagnosis has been possible clinically atpresent, more and more ADPKD sufferers could be diagnosed earlierwithout any clinical symptom or imageological changes. Currently, noeffective treatment can prevent the cysts from forming or enlarging.Finding novel therapeutic interventions to delay the progression of PKDis an urgent task, researchers across the world are seeking novel drugtargets all the time for treatment and prevention of ADPKD.

Muto et al have found that a PPAR-γ agonist pioglitazone, could prolongthe lifespan of Pkd1−/− mices with ADPKD which usually die at the foetalperiod.

In vitro we firstly prove that PPAR-γ agonists 15d-PGJ2, rosiglitazoneor pioglitazone could inhibit the proliferation and induce apoptosis ofADPKD cyst-lining epithelia in a dose-dependent and time-dependentmanner, while the effect on human renal epithelial cells (HKC) isrelatively weak. After administration of rosiglitazone on the Han:SPRDrats, the well documented animal model of ADPKD, treatment group hadlesser proteinuria, kidney weight/body weight, blood urea nitrogen(BUN), cyst index, fibrosis score and inflammatory cells infiltrationcompared with control group by serological and histomorphometricanalysis. The therapeutic mechanism seems not depend on it's metabolismregulation effect on serum glucose and lipid, but through inhibition ofabnormal proliferation, apoptosis, interstitial inflammation andfibrosis. Long-term treatment shows rosiglitazone can prolong thesurvival of Han:SPRD rats (patent application number 200610023398.6).Considering the safety and efficacy of thiazolidinediones in treatmentof animal model of ADPKD and type 2 diabetes patients clinically, PPAR-γagonists may be effective in the treatment of ADPKD.

Thiazolidinediones are now widely used in the treatment of type 2diabetes as PPAR-γ agonists, these include rosiglitazone, pioglitazone,troglitazone, et. Troglitazone was withdrawn in Europe and USA not longafter it went on sale because of severe liver toxicity. Althoughrosiglitazone and pioglitazone show potent activity with lesshepatotoxicity than troglitazone, they also have long-term side effects,such as hepatotoxicity, water-sodium retention, weight gain and possibleexacerbation of congestive heart failure. In vivo, we also found thatrosiglitazone-treated Han:SPRD rats demonstrated heart and liver weightgain with increased volume when they died, indicating that TZDs,administered chronically at high dose, could aggravate water-sodiumretention and cardiac load, resulting in chronic congestive heartfailure and hepatic congestion. Because multiple ADPKD patients mergewith hyperpiesia and myocardial hypertrophy in midanaphase, the sideeffects of this kind of drugs, like aggravating congestive heartfailure, challenges the clinical application in dealing with ADPKD.Since ADPKD sufferers generally need long-term administration or evenlifelong medication, the drug safety is especially important and urgentin these patients.

Recently, researcher also have found that PPAR-γ is expressed in manycancers including the colon, breast, lung and prostate, and PPAR-γligands are generally antiproliferative in these settings. Specifically,PPAR-γ ligands inhibit the proliferation of human breast, prostate,colon and pituitary cancer cells in vitro. Thus PPAR-γ is considered tohave potential antineoplastic effects both in solid cancers and inleukemia through inhibition of cell proliferation, induction ofapoptosis and terminal differentiation or through inhibition ofangiogenesis. Therefore, PPAR-γ ligands may represent a promising, noveltherapeutic approach for certain human malignancies. On the other hand,it's evidenced by the fact that many people in the world are currentlytaking drug as PPAR-γ agonists for long-term control of type 2 diabetes.Thus, in the context of human cancer, it is important to note thatPPAR-γ agonists are relatively nontoxic and well tolerated.

In sum, it is urgent to synthesize novel effective PPAR-γ agonists withless side effects in ADPKD and cancer treatment.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, the present invention isdirected to compounds represented by Structural Formula I andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

X is CH₂, CH(OH), C(O)O, NH, S, or SO₂;

Y is an unsubstituted or substituted phenyl (optionally substituted byone or more of the following groups: C₁-C₆ straight-chain orbranched-chain alkyl, halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, and trifluoromethoxy);

n is 0, 2, 3, or 4;

R₁ is hydro or C₁-C₆ alkyl, C₁-C₈ alkoxyl, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, phenoxy; unsubstituted orsubstituted C₃-C₆ heterocycloalkyl [optionally substituted by one ormore of the following groups: C₁-C₈ alkyl, halogen, C₃-C₆ cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted groups selected from: C₆-C₁₂ heteroaryl containing one ortwo oxygen or nitrogen, C₃-C₆ heterocycloalkyl containing one or twooxygen or nitrogen, (C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing oneor two oxygen or nitrogen, phenyl, (C₅-C₁₂)aryl(C₁-C₆)alkyl (including:benzyl, phenethyl, naphthalen-1-ylmethyl), phenoxy, orcarbobenzoxy(optionally substituted by one or more of the followinggroups: halogen, oxo, C₁-C₆ alkyl, C₁-C₈ alkoxyl, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy; unsubstituted or substituted phenyl or phenoxy whichis substituted by one or more of the following substituents: halogen,C₁-C₆ haloalkyl, amino, mercapto, cyano, nitro, hydroxyl,trifluoromethyl, or trifluoromethoxy)].

R₂ is H, phenyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted amino [(optionally substituted by one or more of thefollowing groups: C₁-C₆ alkyl, C₃-C₇ carbocyclyl, phenyl, benzyl,aralkyl, sulfanilamino, pyridyl, C₁-C₄ acyl), unsubstituted orsubstituted C₃-C₆ heterocycloalkyl which contains one or two oxygen ornitrogen, (optionally substituted by one or more of the followinggroups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, benzyl), unsubstituted orsubstituted phenoxy (optionally substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy);

R₃ is H, C₁-C₈ alkoxyl, halogen, mercapto, cyano, nitro, hydroxyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ straight-chain orbranched-chain alkyl, phenyl, aralkyl, thioureido, unsubstituted orsubstituted amino (optionally substituted by one or more of thefollowing groups: C₁-C₆ straight-chain or branched-chain alkyl, C₃-C₆heterocycloalkyl, phenyl, aralkyl, sulfanilamino, pyridyl, and C₁-C₄acyl);

R₄ is H, C₁-C₆ straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl,mercapto, hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted phenoxy (optionally substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, hydroxyl,trifluoromethyl, and trifluoromethoxy);

R₅ is H, C₁-C₆ straight-chain or branched-chain alkyl, unsubstituted orsubstituted phenyl [optionally substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, C₁-C₆ straight-chain orbranched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano, hydroxyl,trifluoromethyl, trifluoromethoxy, unsubstituted or substituted phenyl(optionally substituted by one or more of the following groups: halogen,C₁-C₄ haloalkyl, amino, mercapto, hydroxyl, trifluoromethyl, andtrifluoromethoxy)];

R₆ is H, C₁-C₆ straight-chain or branched-chain alkyl.

Preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula II

In Structural Formula II, R₁, R₂, R₃, R₄, R₅ and R₆ is defined forStructural Formula I, while R₇ are each, independently, H, C₁-C₆straight-chain or branched-chain alkyl, halo, C₁-C₆ haloalkyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, or trifluoromethoxy;

More preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula III

In Structural Formula III, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined forStructural Formula II,

while R₈ are each, independently, H, C₁-C₆ straight-chain orbranched-chain alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl; unsubstitutedor substituted groups selected from: C₆-C₁₂ heteroaryl containing one ortwo oxygen or nitrogen, C₃-C₆ heterocycloalkyl containing one or twooxygen or nitrogen, (C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing oneor two oxygen or nitrogen, phenyl, (C₅-C₁₂)aryl(C₁-C₆)alkyl (including:benzyl, phenethyl, naphthalen-1-ylmethyl), phenoxy, carbobenzoxy,phenyl, benzyl, phenethyl, or carbobenzoxy [optionally substituted byone or more of the following groups: halogen, C₁-C₆ haloalkyl, C₁-C₆alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano, nitro, hydroxyl,trifluoromethyl, trifluoromethoxy, unsubstituted or substituted phenylor phenoxy (optionally substituted by one or more of the followinggroups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano, hydroxyl,trifluoromethyl, and trifluoromethoxy)];

R₉ is H, C₁-C₈ straight-chain or branched-chain alkyl, halogen, C₁-C₄haloalkyl, amino, mercapto, cyano, hydroxyl, trifluoromethyl, ortrifluoromethoxy.

More preferably, the compounds of the present invention, and with theirrespective pharmaceutical compositions, have a structure represented byStructural Formula IV

In Structural Formula IV, R₂, R₃, R₄, R₆, R₇ and R₉ are as defined forStructural Formula III;

While R₁₀, R₁₁, R₁₂ is H, halogen, C₁-C₆ haloalkyl, C₁-C₆ straight-chainor branched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted phenyl or phenoxy (optionally substituted by one or more ofthe following groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,hydroxyl, trifluoromethyl, and trifluoromethoxy);

Further, R₁₃, R₁₄, R₁₅ is halogen, C₁-C₆ haloalkyl, amino, mercapto,cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted phenyl (optionally substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, hydroxyl,trifluoromethyl, and trifluoromethoxy);

Even more preferable, the compounds of the present invention, and withtheir respective pharmaceutical compositions, have a structurerepresented by Structural Formula V,

R₃, R₄, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are as defined forStructural Formula IV;

While R₁₆ optionally and independently substituted one or two times withC₁-C₆ straight-chain or branched-chain alkyl, C₃-C₇ cycloalkyl, phenyl,aralkyl, sulfanilamino, pyridyl, acyl, unsubstituted or substitutedC₃-C₆ heterocycloalkyl (optionally substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,hydroxyl, trifluoromethyl, and trifluoromethoxy);

In a second aspect of the present invention, the present inventionprovides a process for preparing a compound of Formula (I) or apharmaceutically acceptable salt thereof, which process (whereinvariable groups are, unless otherwise specified, as defined in formula(I)) comprises of:

In the presence of cesium carbonate, compound (Ia) is treated withcompound (Ib) in a polar solvent at a temperature of about 60° C. toabout 100° C., to form compound (I):

while, R₁˜R₆ are as defined for Structural Formula I;

In one embodiment, the customary organic solvents which do not changeunder the reaction conditions are selected from: 1,2-dimethoxyethane,THF, DMF, dichloromethane, acetone, EA, methanol, ethanol, water, ormixed solvent such as THF, water, methanol or the mixture thereof.

In another embodiment of the present invention, the reaction temperatureis between 60° C. and 100° C., preferably between 70° C. to 90° C.; thereaction time is 15 minutes to 2 days, preferable is 30 minutes to 1day.

Compounds of Structural Formula (II) have been formed by the proceduresherein:

In the presence of cesium carbonate, compound (Ia) is treated withcompound (IIa) in a polar solvent at a temperature of about 60° C. toabout 100° C., to form compound (II):

while, R₁-R₃ and R₄-R₇ are as defined for Structural Formula II;

While R₄ is H, Compounds of Structural Formula (II) have been formed bythe procedures herein:

a) synthesize α-substituted phenylpropionate ester:

b) prepare substituted or unsubstituted pyridine

-   -   prepare the pyridine by condensation reaction

While R₂ is substituted amino, R₃ is H, R₁₆ is as defined in StructuralFormula IV;

c) prepare 4-(pyrimidinyl-oxy)-phenylpropionate ester:

While all substitutes in the reaction are defined for StructuralFormulas above beside R₄;

While R₄ is methyl, Compounds of the Structural Formula (II) have beenformed by the procedures herein:

a) prepare the α,α-substituted phenylpropionate ester:

b) prepare substituted or unsubstituted pyridine:

-   -   prepare the pyridine by condensation reaction

While R₂ is substituted amino, R₃ is H, R₁₆ is as defined in StructuralFormula IV;

c) prepare 4-(pyrimidinyl-oxy)-phenylpropionate ester:

While all substitutes in the reaction are defined for StructuralFormulas above;

In a third aspect of the present invention, the present invention alsorelates to pharmaceutical compositions which comprising: at least onecompound selected from the compound of the present invention,enantiomer, racemic body, pharmaceutically acceptable salts, solvatesand hydrates thereof; and pharmaceutically acceptable carrier, excipientor retarder.

In another embodiment, pharmaceutical compositions of the presentinvention could be in many forms, such as troche, capsule, powder,sirup, solution, suspending agent or aerosol.

In another embodiment, most suitably the composition will be formulatedin unit dose form. Such unit dose will normally contain an amount of thecompound of formula (I), enantiomer, racemic body, pharmaceuticallyacceptable salts, solvates and/or hydrates thereof in the range from0.05 to 500 mg, more usually 0.5 to 200 mg, and more especially 0.1 to100 mg.

In another embodiment, pharmaceutical compositions according to thepresent invention, may comprise typically the active ingredientcomprising the formula (I) enantiomer, racemic body, pharmaceuticallyacceptable salts, solvates and/or hydrates thereof in an amount of atleast 0.001-99.9 weight percent, more usually 0.01-99 weight percent,and more especially 0.1-90 weight percent. A weight percent is a ratioby weight of total by weight of total composition.

In further embodiment, pharmaceutical compositions could contain one ormore other medicine in the treatment and prevention of polycystic kidneyand cancer: ACE inhibitor, PPAR-γ agonist, for example, Enalapril,Benazepril, and Rosiglitazone. In another embodiment, pharmaceuticalcompositions contains: (a) as the active ingredient of compound ofFormula Ienantiomer, racemic body, pharmaceutically acceptable salts,solvates and hydrates; (b) pharmaceutically acceptable carrier,excipient or retarder.

In further embodiment, pharmaceutical compositions according to thepresent invention, may comprise typically the active ingredientcomprising the formula (I) enantiomer, racemic body, pharmaceuticallyacceptable salts, solvates and hydrates of which an amount of at least0.001-99.9 weight percent, more usually 0.01-99 weight percent, and moreespecially 0.1-90 weight percent. A weight percent is a ratio by weightof total by weight of total composition.

In further embodiment, pharmaceutical compositions could contain one ormore other medicine in the treatment and prevention of polycystic kidneyand cancer: ACE inhibitor, PPAR-γ agonist, for example, Enalapril,Benazepril, Rosiglitazone.

In a fourth aspect of the present invention, the present inventionprovides a method for the preparation of a pharmaceutical composition,which comprises the step of mixing an amount of the compounds of thepresent invention, enantiomer, racemic body, pharmaceutically acceptablesalts, solvates and/or hydrates thereof with pharmaceutically acceptablecarrier, excipient or retarder and form a pharmaceutical composition.The amount of the compounds of the present invention, enantiomer,racemic body, pharmaceutically acceptable salts, solvates and/orhydrates thereof is at least 0.001-99.9 weight percent, more usually0.01-99 weight percent, and more especially 0.1-90 weight percent, basedon the total weight of the pharmaceutical composition.

The compounds of the present invention and pharmaceutically acceptablesalts, solvates and hydrates thereof are believed to be effective inautosomal dominant polycystic kidney disease (ADPKD), autosomalrecessive polycystic kidney disease (ARPKD), and cancer.

Therefore, in a fifth aspect of the present invention, the presentinvention provides a use of the compounds of the present invention inthe preparation of a pharmaceutical composition for the treatment ofpolycystic kidney and/or cancer.

In some embodiments, said polycystic kidney is selected from autosomalrecessive polycystic kidney disease or autosomal dominant patternpolycystic kidney disease. In other embodiments, said cancer is selectedfrom colon, breast, lung and prostate, pituitary cancer, or leukemia.

In a sixth aspect of the present invention, the present inventionprovides a method for the treatment of the subject suffering frompolycystic kidney and/or cancer, which comprising administrating aneffective amount of the pharmaceutical composition of the presentinvention to the subject in need of such treatment.

In some embodiments, said polycystic kidney is selected from autosomalrecessive polycystic kidney disease or autosomal dominant patternpolycystic kidney disease. In other embodiments, said cancer is selectedfrom colon, breast, lung and prostate, pituitary cancer, or leukemia.

In further aspect of the present invention, the present inventionprovides a pharmaceutical composition for treating polycystic kidneyand/or cancer, which comprising:

(i) at least one compound selected from the compound, pharmaceuticallyacceptable salts, solvates, or hydrates thereof of the invention; and

(ii) pharmaceutically acceptable carrier, excipient or retarder.

In some embodiments, said polycystic kidney is selected from autosomalrecessive polycystic kidney disease or autosomal dominant patternpolycystic kidney disease. In other embodiments, said cancer is selectedfrom colon, breast, lung and prostate, pituitary cancer, or leukemia.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is the Kaplan-Meier plot of Han: SPRD long-term treatment withthe compound 2.

DETAILED DESCRIPTION OF THE INVENTION

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt thereof, are effective PPARγ agonist,and accordingly have value in the treatment of polycystic kidney.

Active Ingredient

In the present invention, the technical terms “Active ingredient”,“Active compound”, “the compounds of the invention”, “a new PPARagonist” can be used interchangeably, these technical terms, are theStructural Formula I pyrimidinyl-aryl propionic acid and theirenantiomer, racemic body, pharmaceutically acceptable salts, solvatesand hydrates thereof.

Pharmaceutical Composition

The present invention also includes pharmaceutical compositions treatingor preventing polycystic kidney, which contain: (a) as the activeingredient of compound of Formula I in treatment and prevention ofpolycystic kidney; (b) pharmaceutically acceptable carrier, excipient orretarder.

The term “contain” refers to one or more of the compounds of theinvention above in combination with one or more pharmaceuticallyacceptable carriers. Thus, the term “main comprise of” and “comprise of”include the term “contain”.

The term “pharmaceutically acceptable” means in the present descriptionbeing useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable andincludes being useful for veterinary use as well as human pharmaceuticaluse.

As use herein, “pharmaceutically acceptable carrier” refers to solvent,suspending agent or excipient that transmit active ingredient orpharmaceutically acceptable salts to human or veterinary. The carriercould be liquid or solid.

As use herein, Pharmaceutical compositions according to the presentinvention, may comprise typically the active ingredient comprising theformula (I) or pharmaceutically acceptable carrier or excipient orretarder of which an amount of at least 0.001-99.9 weight percent, moreusually 0.01-99 weight percent, and more especially 0.1-90 weightpercent. A weight percent is a ratio by weight of total by weight oftotal composition.

In another embodiment, a typical pure compounds of the formula (I) orpharmaceutically acceptable carrier or excipient or retarder comprisesgreater than 65% by weight of total weight, the others comprise 0.5-40%,or more preferably 1-20%, or even more preferably 1-10%.

As use herein, most suitably the composition will be formulated in unitdose form. Such unit dose will normally contain an amount of thecompound of formula (I), enantiomer, racemic body, pharmaceuticallyacceptable salts, solvates and hydrates in the range from 0.05 to 500mg, more usually 0.5 to 200 mg, and more especially 0.1 to 100 mg.

Further, as used herein, pharmaceutical compositions could contain oneor more other medicine in the treatment and prevention of polycystickidney: ACE inhibitor, PPAR-γ agonist and so on, for example, Enalapril,Benazepril, and Rosiglitazone.

When combination treatment or prevention of polycystic kidney comprisesthe compound of Formula (I), dosage of the active ingredient is used asusually, or even lower.

Form of Medication and Dose

Pharmaceutical compositions of the present invention could be in manyforms, such as troche, capsule, powder, sirup, solution, suspendingagent or aerosol, compound of formula (I) could be maintained insuitable solid, liquid carrier or dilution. Pharmaceutical compositionsof the present invention could also be deposited in suitable disinfectorof injection or drop.

The compounds of formula (I) or pharmaceutical compositions of theinvention can also be administered in a targeted drug delivery system,such as, for example, ora, nose, skin, lung or gastrointestinal tract.Oral is optional route of administration, usually 0.5 mg-200 mg/kg onceor several times a day. In spite of administration, the suitable dosageis decided according to treatment. The amount of compound or compositionadministered to a patient will vary depending upon the compound used,the manner of administration and the state of the patient.

On the other hand, the active ingredient may be administered in anamount in the range of about 1-300 mg/kg per day, typically administered1 to 3 times per day, or administered by the technique of delayedrelease. Especially most mammal, the unit dosage per day contain from5-1000 mg, more preferably 10-500 mg. For oral administration, a dosageof the pharmaceutically acceptable carrier contain from 1-200 mg of theactive ingredient. In therapeutic applications, the desired dose mayconveniently be presented as divied doses administered at appropriateintervals.

The compounds of formula (I) or pharmaceutical compositions of theinvention can also be administered in a targeted drug delivery system byoral, intravenous, intramuscularly, subcutaneously. According to beprone to prepare and administration, the more preferable pharmaceuticalcompositions is solid, especially troche and capsule. Oraladministration is more preferable.

A solid carrier can be starch, lactose, calcium phosphate, fibrin,sucrose and bolus alba, and a liquid carrier can be aqua sterilisata,polyethylene glycol, surface active agent and edible oil (corn oil,arachis oil and benne oil) and so on. Adjuvant could also be used, forexample, flavoring agent, pigment, antiseptic and antioxidant such asvitamin E, vitamin C, BHT and BHA.

The compounds of formula (I) or pharmaceutical compositions of theinvention can also be administered in a targeted drug delivery system byintestines and stomach or abdominal cavity. Solution or suspension ofthe active ingredient can also be prepared in water containing suitablesurfactant (such as hydroxypropyl cellulose). Its dispersed liquid canalso be prepared in glycerin, polyethylene glycol, or mixture of them.Under ordinary conditions of storage and use, these preparations containa preservative to prevent the growth of microorganisms.

The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans. The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that each svringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against anycontamination. The carrier can be solvent or dispersion mediumcontaining, for example, eater, preferably in physiologically compatiblebuffers such as Hank's solution, Ringer's solution, or physiologicalsaline buffer, ethanol, polyol (e.g. glycerol, propylene glycol andliquid polyethylene glycol), propylene glycol and suitable mixturesthereof, and vegetable oils.

The compounds of formula (I) and their pharmaceutically acceptablesalts, solvates can be used in combination with other medicine oftreatment or prevention of polycystic kidney. When two or more medicineis used, the effect of drug combination is generally better than that ofsignal drug.

Synthesis and Processes

General Procedures of Compound (I):

In the presence of cesium carbonate, compound (Ia) is treated withcompound (Ib) in a polar solvent at a temperature of about 60° C. toabout 100° C., to form compound (I):

While, all substitutes in the reaction are defined above.

In one embodiment, the customary organic solvents which not change underthe reaction conditions: 1,2-dimethoxyethane, THF, DMF, dichloromethane,acetone, EA, methanol, ethanol, water, or mixed solvent such as THF,water and methanol.

In another embodiment, the reaction temperature is between 60° C. and100° C., preferably between 70° C. to 90° C.; the reaction time is 15minutes to 2 days, preferable is 30 minutes to 1 day.

General Procedures of Compound (II):

1. while R₄ is H, the Compounds have been formed by the proceduresherein:

a) α-substituted phenylpropionate ester:

-   -   a1) Form the enol by potassium tert-butoxide in a tert-butyl        alcohol solvent,    -   a2) Form the phenol by treated with hydrogen in the presence of        palladium on carbon (Pd/C) catalyst,

b) prepare substituted or unsubstituted pyridine:

-   -   b1) At a temperature of 0° C., the 2,4,6-Trichloro-pyrimidine        was dissolved in an anhydrous aprotic solvent such as acetone or        THF, added the amino, to form the 2-amino-pyrimidine,    -   b2) In the presence of cesium carbonate/DMF, to form the        pyrimidine,

-   -   Or prepare the pyridine by condensation reaction    -   b1′) the diethyl malonate and amidine was heated to cyclize in        the present of    -   b2′) use hot POCl₃ to chloridate,    -   b3′) In the presence of cesium carbonate/DMF, to form the        pyrimidine,

c) prepare 4-(pyrimidinyl-oxy)-phenylpropionate ester:

-   -   c1) In the presence of cesium carbonate/DMF, to form the        pyrimidine,    -   c2) In the presence of THF/CH₃OH/H₂O/KOH, hydrolyze to form the        acid,

2. while R₄, R₅ is unsubstituted or substituted phenyl, the compoundshave been formed by the procedures herein:

a) prepare the α,α-substituted phenylpropionate ester:

-   -   a1) in the presents of potassium carbonate and acetone, to form        the ester,    -   a2) at a temperature of about −78° C., aldol condensation to        form the enol, in the present of LDA/THF,    -   a3) an ether complex of boron trifluoride and triethylsilane to        remove hydroxy group,    -   a4) Form the phenol by treated with hydrogen in the presence of        palladium on carbon (Pd/C) catalyst,

b) prepare substituted or unsubstituted pyridine:

-   -   b1) At a temperature of 0° C., the 2,4,6-Trichloro-pyrimidine        was dissolved in an anhydrous aprotic solvent such as acetone or        THF, added the amino, to form the 2-amino-pyrimidine,    -   b2) In the presence of cesium carbonate/DMF, to form the        pyrimidine,

-   -   Or prepare the pyridine by condensation reaction    -   b1′) the diethyl malonate and amidine was heated to cyclize in        the present of EtONa/EtOH    -   b2′) use hot POCl₃ to chloridate,    -   b3′) In the presence of cesium carbonate/DMF, to form the        pyrimidine,

c) prepare 4-(pyrimidinyl-oxy)-phenylpropionate ester:

-   -   c1) In the presence of cesium carbonate/DMF, to form the        pyrimidine,    -   c2) In the presence of THF/CH₃OH/H₂O/KOH, hydrolyze to form the        acid,

As used herein, the reaction described above may be performed understandard conditions. For example, the solvent generally is inertsolvent: 1,2-dimethoxyethane, THF, DMF or mixed solvent and so on. Thereaction temperature is carried out between room temperature andrefluence temperature; and the reaction time is half an hour to 1 day,which can be change according to the material, solvent and reactiontemperature.

As used herein, the term “room temperature” is environmentaltemperature, generally is 25°.

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, “alkenyl” is straight-chain or branched-chain alkenylhaving from two to six carbon atoms, such as ethylene, allyl, acryl,isopropenyl, 1-butenyl, 2-butenyl and so on;

The term “cycloalkyl groups”, as used herein, include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;

As used herein, “C₁₋₆ alkyl” is straight-chain or branched-chain alkylhaving from one to four carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, Sec-butyl, Tert-butyl, pentyl, hexyland soon;

The term “C₁₋₈ alkoxyl” is straight-chain or branched-chain alkoxylhaving from one to four carbon atoms, such as methoxyl, ethoxyl,propoxyl, isopropoxyl, butoxyl, isobutoxyl, Sec-butoxyl, Tert-butoxyl,pentyl, hexyl, heptyl, octyl and so on;

As used herein, “halogen” include fluoro, chloro, bromo or iodo;

The term “C₁-C₆ haloalkyl”, as used herein, is C₁₋₆ alkyl substituent byone to six same or different halogen, such as trifluoromethyl,pentafluoroethyl, and so on;

The term “C₁₋₄ acyl”, as used herein, is straight-chain orbranched-chain acyl having from one to four carbon atoms, such asformyl, acetyl, propionyl, butyryl, isobutyryl, and so on;

The term “aryl”, as used herein, include aralkyl having simple to threerings, such as phenyl, naphthyl, and so on;

The term “aralkyl”, as used herein, is C₁₋₆ alkyl substituent by aryl;

As used herein, “unsubstituted or substituted heteroaryl which containsone or two oxygen or nitrogen” include furyl, pyridyl, pyrimidinyl,pyrrolyl, pyrazinyl, pyridazinyl, and so on;

As used herein, “C₃-C₆ heterocycloalkyl” include pyrrolidinyl,piperidinyl, morpholinyl, piperazidinyl, and so on;

In the instant invention, Compounds of the Structural Formula (I) couldbe unsubstituted or substituted by one to three group described above,which usually is selected from halogen, C₁₋₄ alkyl, amino, hydroxyl,trifluoromethyl, trifluoromethoxy and so on.

Main advantages of the invention are:

(1) Compounds of the invention are new PPAR-γ agonists, by transienttransfection and transcription assay;

(2) According to experiments in vivo and vitro, compounds of theinvention are the same as or even more therapeutic efficacy in treatmentof polycystic kidney and cancrer, meanwhile decreasing side-effect,compared to current medicine. Thus, compounds of the invention areespecially practical importance in treatment of polycystic kidney andcancer.

EXEMPLIFICATION Exemplified Compounds Example 1rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionicacid

The tile compound, shown above, was made as described below.

Step A 3-(4-Benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester

P(OEt)₃ was added dropwise to a mixture of tent-butyl methyl ether 55mL) and potassium tert-butoxide (4.65 g, 41.4 mmol) under a nitrogenatmosphere at 20-30° C. 4-Benzyloxybenzaldehyde (4.61 g, 21.7 mmol) wasadded in portions to this mixture at 5° C. followed by the addition oftert-butyl alcohol (6.70 g). The reaction mixture was allowed to reach15° C. and stirred at this temperature for approximately 30 min, afterwhich the reaction was completed (as judged by TLC). Water (30 mL) wasadded at 5-10° C., and the phases were allowed to separate. The organicphase was concentrated in vacuo, and ethanol (30 mL) was added to thestirred solution. After crystallization had occurred, water (18 mL) wasadded to the suspension. The light-yellow title compound was filteredoff, washed with ethanol/water (1:1 v/v), and dried in vacuo to yield6.52 g (92% yield).

¹H NMR, 400 MHz (acetone-d6): δ 1.12 (t, J=7 Hz), 1.32 (t, J=7 Hz), 1.33(t, J=7 Hz), 3.91 (q, J=7 Hz), 4.00 (q, J=7 Hz), 4.12 (q, J=7 Hz), 4.24(q, J=7 Hz), 5.12 (s), 5.17 (s), 6.10 (s), 6.93 (s), 6.94 (d, J=9 Hz),7.05 (d, J=9 Hz), 7.15 (d, J=9 Hz), 7.32-7.42 (m), 7.46-7.50 (m), 7.81(d, J=9 Hz).

Step B 2-Ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester

Ethyl E/Z-3-(4-benzyloxyphenyl)-2-ethoxyacrylate (20.0 g, 61.3 mmol)dissolved in tert-butyl methyl ether (40 mL) charged with palladium oncarbon (5%) (1.0 g, Engelhard Tech code no. 4531) was hydrogenated withvigorous stirring at atmospheric pressure at room temperature for 2-3days. The catalyst was filtered off and washed with a few milliliters oftent-butyl methyl ether. The combined filtrates were concentrated invacuo to yield 14.5 g (99% yield) of the title compound as a viscousoil, which crystallizes upon standin.

¹H NMR, 400 MHz (acetone-d6): δ 1.09 (t, 3H, J=7 Hz), 1.17 (t, 3H, J=7Hz), 2.83-2.91 (m, 2H), 3.35 (d, q, 1H, J=7 and 14 Hz), 3.55 (d, q, 1H,J=7 and 14 Hz), 3.98 (d, d, 1H, J=4, 7 Hz), 4.10 (q, 2H, J=7 Hz), 6.74(d, 2H, J=9 Hz), 7.06 (d, 2H, J=9 Hz), 8.08 (s, 1H). ¹³C NMR(acetone-d6), 100 MHz: δ 4.9, 15.9, 39.5, 61.3, 66.6, 81.5, 116.2,129.3, 131.6, 157.3, 173.0.

Step Crac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester

Phenol (33.3 mmol),4-(4-Benzyl-piperazin-1-yl)-6-chloro-pyrimidin-2-ylamine (33.3 mmol) andCs₂CO₃ (36.6 mmol) were combined in anhydrous N,N-dimethylformamide(DMF) (40 mL) and stirred at 90° C. in dry atmosphere over night. TheDMF was removed in vacuo, the residue was dissolved in acetone, andrac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester (13.2 g, 70%) is crystallized form acetone.

Step Drac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionicacid

rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionicacid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solventin the presence of an excess of aqueous potassium hydrate, the reactionis allowed to proceed for about 20 h. After most of the solve wasremoved in vacuo, the aqueous solution was acidified to pH 6, the whiteproduct was precipitated, then filtered through celite,rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionicacid (95%) was collected.

Example 2rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The tile compound, shown above, was made as described below.

Step A 2-Phenoxypropionic acid ethyl ester

Phenol (24.28 g, 0.25 mol), potassium carbonate (39.2 g 0.28 mol), andethyl 2-bromoproionate (46.7 g, 0.25 mol) were combined in acetone (200mL) and stirred at room temperature over night. The acetone was removedin vacuo, the residue was purified in silica to provide a golden oil (50g, 90%), R_(f)=0.80 in 10:1 ethyl acetate: petroleum ether.

¹H NMR (250 MHz, CDCl₃): δ 1.24 (t, 3H, J=7.2 Hz), 1.66 (d, 3H, J=6.1Hz), 4.26 (q, 2H, J=7.2 Hz), 4.79 (q, 1H, J=6.1 Hz), 6.93 (d, 2H, J=7.8Hz), 7.02 (t, 1H, J=7.9 Hz), 7.31 (d, 2H, J=7.8 Hz); MS [EI⁺] 195(M+H)⁺.

Step B 4-Benzyloxy-benzaldehyde

4-hydroxy-benzaldehyde (57.64 g, 0.47 mol) and potassium carbonate (71.6g, 0.51 mol), which were combined in acetone (200 mL), were reacted withbenzyl bromine (80.73 g, 0.51 mol) and stirred at room temperature overnight. The acetone was removed in vacuo, and the4-Benzyloxy-benzaldehyde (71.6 g), as a white solid, is crystallizedform ethyl acetate.

Step C 2-Phenoxy-3-(4-benzyloxyphenyl)-3-hydroxy-2-methyl-propionic acidethyl ester

A solution of lithium diisopropylamide (LDA) (26 mL, 52 mmol, 2 M intetrahydrofuran) was cooled to −78° C. and then added to a solution of2-Phenoxypropionic acid ethyl ester (10 g, 51 mmol) in anhydroustetrahydrofuran (THF) (80 mL) also cooled to −78° C. under an atmosphereof nitrogen. After 30 min, 4-benzyloxybenzaldehyde (10 g, 47 mmol) wasadded in one portion. After stirring over night, the reaction mixturewas quenched with saturated solution of aqueous NH₄Cl (10 mL) and themixture allowed to warm to ambient temperature. The biphasic mixture wasdiluted with dichloromethane and partitioned, and the organic layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified in silica to provide colorless oil (8.9 g, 47%),R_(f)=0.30 in 10:1 ethyl acetate: petroleum ether.

Step D 2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethylester

2-Phenoxy-3-(4-benzyloxyphenyl)-3-hydroxy-2-methyl-propionic acid ethylester (20.4 g, 50 mmol) in anhydrous CH₂Cl₂ (200 mL) was cooled to 0° C.and treated with BF₃-Et₂O (6.12 mL, 50 mmol) and triethylsilane (8.16mL, 9.5 mmol). The mixture was stirred over night. Saturated aqueousNa₂CO₃ (75 mL) was added and the mixture was stirred vigorously. Thesolution was partitioned and the organic layer was washed twice withwater and brine, dried over MgSO₄ and concentrated in vacuo, thenpurified in silica to provide a colorless oil (9.9 g, 51%)

¹HNMR (300 MHz, CDCl₃) δ1.22 (t, 3H, J=7.1 Hz), 1.40 (s, 3H), 3.13 (d,1H, J=13.8 Hz), 3.26 (d, 1H, J=13.8 Hz), 4.22 (q, 2H, J=7.1 Hz), 5.05(s, 2H), 6.83 (d, 2H), 6.91 (d, 2H), 6.98 (t, 1H), 7.17˜7.24 (m, 5H),7.34 (t, 1H), 7.36˜7.42 (m, 3H).

Step E 3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester

2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester(24.1 g, 59.3 mmol) was dissolved in ethanol (200 mL) and treated with10% palladium on carbon (2.41 g), and then stirred under an atmosphereof hydrogen for 20 h. The suspension was filtered through celite andconcentrated in vacuo to produce3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl estercolorless oil (16.9 g, 95%).

¹H NMR δ1.22 (t, 3H, J=7.1 Hz), 1.40 (s, 3H), 3.09 (d, 1H, J=13.5 Hz),3.26 (d, 1H, J=13.5 Hz), 4.02 (q, 2H, J=7.1 Hz), 5.01 (s, 2H), 6.81˜6.93(m, 3H), 7.14-7.22 (m, 2H), 7.27˜7.40 (m, 31-1).

Step F 4-(4-Benzyl-piperazin-1-yl)-6-chloro-pyrimidin-2-ylamine

1-Benzyl-piperazine (5.86 g, 33.3 mmol), 2-amino-4,6-dichloro-pyrimidine(5.46 g, 33.3 mmol) and Cs₂CO₃ (10.8 g, 36.6 mmol) were combined inanhydrous N,N-dimethylformamide (DMF) (50 mL) and stirred at 90° C. indry atmosphere for 5 h. The DMF was removed in vacuo, the residue wasdissolved in acetone, and4-(4-Benzyl-piperazin-1-yl)-6-chloro-pyrimidin-2-ylamine (8.5 g, 86%)was is crystallized form acetone.

Step Grac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester

Phenol (10 g, 33.3 mmol),4-(4-Benzyl-piperazin-1-yl)-6-chloro-pyrimidin-2-ylamine (10 g, 33.3mmol) and Cs₂CO₃ (10.8 g, 36.6 mmol) were combined in anhydrousN,N-dimethylformamide (DMF) (40 mL) and stirred at 90° C. in dryatmosphere over night. The DMF was removed in vacuo, the residue wasdissolved in acetone, and3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester. (13.2 g, 70%) is crystallized form acetone.

Step Hrac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solventin the presence of an excess of aqueous potassium hydrate, the reactionis allowed to proceed for about 20 h. After most of the solve wasremoved in vacuo, the aqueous solution was acidified to pH 6, the whiteproduct was precipitated, then filtered through celite,rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid (11 g, 95%) was collected.

¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 3.00 (d, d, 4H), 3.20 (q, 2H),3.70 (d, d, 4H), 4.05 (s, 2H), 5.19 (s, 1H), 6.88˜7.06 (m, 5H),7.20˜7.37 (m, 4H), 7.46˜7.55 (m, 5H), EI-MS: m/e 539 (M⁺).

Example 3S-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester were separated by chiral chromatography using aChiralpak AD 4.6 mm×250 mm column.

S-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solventin the presence of an excess of aqueous potassium hydrate, the reactionis allowed to proceed for about 20 h. After most of the solve wasremoved in vacuo, the aqueous solution was acidified to pH 6, the whiteproduct was precipitated, then filtered through celite,S-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid (10 mg) was collected. ee: 99% (AD-H, 0.46 cm I.D.×25 cm)

¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 3.00 (d, d, 4H), 3.20 (q, 2H),3.70 (d, d, 4H), 4.05 (s, 2H), 5.19 (s, 1H), 6.88˜7.06 (m, 5H),7.20˜7.37 (m, 4H), 7.46˜7.55 (m, 5H), EI-MS: m/e 539 (M⁺).

Example 4R-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester were separated by chiral chromatography using aChiralpak AD 4.6 mm×250 mm column.

R-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solventin the presence of an excess of aqueous potassium hydrate, the reactionis allowed to proceed for about 20 h. After most of the solve wasremoved in vacuo, the aqueous solution was acidified to pH 6, the whiteproduct was precipitated, then filtered through celite,R-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid (10 mg, 95%) was collected. ee: 99% (AD-H, 0.46 cm I.D.×25 cm)

¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 3.00 (d, d, 4H), 3.20 (q, 2H),3.70 (d, d, 4H), 4.05 (s, 2H), 5.19 (s, 1H), 6.88˜7.06 (m, 5H),7.20˜7.37 (m, 4H), 7.46˜7.55 (m, 5H), EI-MS: m/e 539 (M⁺).

Example 53-{4-{2-Amino-6-[4-(1,3-dihydro-isobenzofuran-5-ylmethyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 190-192° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 3.00 (t, 4H),3.20 (m, 2H), 3.70 (t, 4H), 4.05 (s, 2H), 5.19 (s, 1H), 5.90 (d, 2H),6.88˜7.06 (m, 5H), 7.20˜7.37 (m, 4H), 7.46˜7.55 (m, 3H); EI-MS: m/e 583(M⁺), 135 (100%).

Example 63-{4-[2-Amino-6-(4-(naphthalen-1-ylmethyl)-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 93-94° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.34 (s, 3H), 2.50 (t, 4H, J=5.1Hz), 3.09 (d, 1H, J=13.5 Hz), 3.21 (d, 1H, J=13.5 Hz), 3.27 (t, 4H,J=5.1 Hz), 3.93 (s, 2H), 5.47 (s, 1H), 6.82 (d, 1H, J=8.1 Hz), 6.95˜7.01(m, 2H), 7.23˜7.28 (m, 3H), 7.46˜7.58 (m, 6H), 7.87˜7.96 (m, 3H), 8.28(d, 1H, J=7.5 Hz); EI-MS: m/e 589 (M⁺), 141 (100%).

Example 73-{4-{2-Amino-6-[4-(4-fluoro-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 107-109° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 2.58 (t, 4H),3.15 (q, 2H), 3.53 (t, 4H), 3.65 (s, 2H), 5.15 (s, 1H), 6.9 (t, 3H),7.00 (d, 2H), 7.18 (t, 2H), 7.35 (d, 2H), 7.60 (q, 4H).

EI-MS: m/e 557 (M⁺), 94 (100%).

Example 83-{4-{2-Amino-6-[4-(4-trifluoromethyl-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 114-115° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.50 (t, 4H,J=5.1 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.53 (t,4H, J=5.1 Hz), 3.65 (s, 2H), 5.25 (s, 1H), 6.9 (m, 3H), 7.00 (d, 2H,J=8.4 Hz), 7.18 (t, 2H, J=7.8 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.58 (d, 2H,J=8.1 Hz), 7.62 (d, 2H, J=8.1 Hz); EI-MS: m/e 607 (M⁺), 94 (100%).

Example 93-{4-{2-Amino-6-[4-(3-methyl-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 115-116° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.34 (s, 3H),2.50 (t, 4H, J=5.1 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5Hz), 3.60 (t, 4H, J=5.1 Hz), 3.94 (s, 2H), 5.32 (s, 1H), 6.9 (m, 4H),7.00 (d, 2H, J=8.4 Hz), 7.16˜7.25 (m, 5H), 7.33 (d, 2H, J=8.4 Hz);EI-MS: m/e 553 (M⁺), 94 (100%).

Example 103-{4-{2-Amino-6-[4-(3-trifluoromethyl-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 97-98° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.53 (t, 4H, J=5.1Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.53 (t, 4H,J=5.1 Hz), 3.70 (s, 2H), 5.25 (s, 1H), 6.9 (m, 3H), 7.00 (d, 2H, J=8.4Hz), 7.18 (t, 2H, J=7.8 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.55˜7.69 (m, 4H);EI-MS: m/e 607 (M⁺), 94 (100%).

Example 113-{4-{2-Amino-6-[4-(3-chloro-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 87-89° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.30 (s, 3H), 2.50 (t, 4H,J=5.1 Hz), 3.13 (d, 1H, J=13.5 Hz), 3.22 (d, 1H, J=13.5 Hz), 3.18 (q,2H, J=13.5 Hz), 3.63 (t, 4H, J=5.1 Hz), 4.41 (s, 2H), 5.46 (s, 1H), 6.83(d, 2H, J=8.1 Hz), 6.90 (t, 1H, J=7.5 Hz), 6.96 (d, 2H, J=8.4 Hz),7.19˜7.38 (m, 8H); EI-MS: m/e 573 (M⁺), 94 (100%).

Example 123-{4-{2-Amino-6-[4-(3-fluoro-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 113-115° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 2.58 (t, 4H),3.15 (q, 2H), 3.53 (t, 4H), 3.65 (s, 2H), 5.15 (s, 1H), 6.92 (t, 3H),7.00 (d, 2H), 7.18 (t, 2H), 7.35 (d, 2H), 7.60 (m, 4H).

EI-MS: m/e 557 (M⁺), 94 (100%).

Example 133-{4-{2-Amino-6-[4-(4-chloro-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 103-105° C.; ¹HNMR (400 MHz, CD₃OD): δ 1.40 (s, 3H), 2.95 (t, 4H,J=5.1 Hz), 3.20 (d, 1H, J=13.5 Hz), 3.38 (d, 1H, J=13.5 Hz), 3.70 (t,4H, J=5.1 Hz), 4.05 (s, 2H), 5.38 (s, 1H), 6.82 (m, 1H), 6.93 (m, 2H),7.03 (m, 2H), 7.18 (m, 2H), 7.27-7.38 (m, 6H); m/e 573 (M⁺), 94 (100%).

Example 143-{4-{2-Amino-6-[4-(4-tert-butyl-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 96-97° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.26 (s, 9H), 1.33 (s, 3H),2.36 (t, 4H, J=5.1 Hz), 3.18 (m, 2H), 3.26 (s, 2H), 3.44 (t, 4H, J=5.1Hz), 5.45 (s, 1H), 6.83 (d, 2H, J=8.4 Hz), 6.93˜6.99 (m, 3H), 7.21 (m,5H), 7.35 (m, 3H); EI-MS: m/e 595 (M⁺), 147 (100%).

Example 153-{4-{2-Amino-6-[4-(4-bromo-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 112-114° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 2.84 (t, 4H,J=5.1 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.63 (t,4H, J=5.1 Hz), 3.91 (s, 2H), 5.38 (s, 1H), 6.90 (m, 3H), 7.01 (d, 2H,J=8.7 Hz), 7.22 (m, 2H), 7.36 (d, 2H, J=8.7 Hz), 7.58 (d, 2H, J=8.7 Hz),7.62 (d, 2H, J=8.7 Hz); EI-MS: m/e 617 (M⁺), 94 (100%).

Example 163-{4-{2-Amino-6-[4-(3-bromo-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 119-120° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.40 (s, 3H), 3.25 (q, 2H,J=13.5 Hz), 3.53 (t, 4H, J=5.1 Hz), 3.63 (t, 4H, J=5.1 Hz), 5.52 (s,1H), 6.69 (t, 1H, J=6.6 Hz), 6.80 (d, 1H, J=9.0 Hz), 6.90 (d, 2H, J=7.1Hz), 6.96 (d, 1H, J=6.6 Hz), 7.04 (d, 1H, J=7.5 Hz), 7.23 (t, 2H, J=7.5Hz), 7.36 (d, 2H, J=7.5 Hz), 7.57 (t, 1H, J=8.4 Hz), 8.07 (m, 1H);EI-MS: m/e 618 (M⁺), 94 (100%).

Example 173-{4-{2-Amino-6-[4-(3-phenoxy-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Example 183-{4-{2-Amino-6-[4-(2-oxo-2-phenyl-ethyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Mp: 107-108° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.32 (s, 3H), 3.30˜3.62 (m,10H), 3.68 (s, 2H), 5.53 (s, 1H), 6.83˜7.02 (m, 5H), 7.21˜7.25 (m, 4H),7.62 (d, 2H, J=7.2 Hz), 7.62 (t, 1H, J=7.5 Hz), 7.62 (d, 2H, J=8.4 Hz);EI-MS: m/e 567 (M⁺)

Example 193-{4-[2-Amino-6-(4-pyridin-2-yl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 110-111° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.40 (s, 3H), 3.20 (d, 1H,J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.53 (t, 4H, J=5.1 Hz), 3.63 (t,4H, J=5.1 Hz), 5.52 (s, 1H), 6.69 (t, 1H, J=6.6 Hz), 6.80 (d, 1H, J=9.0Hz), 6.90 (d, 2H, J=7.1 Hz), 6.96 (d, 1H, J=6.6 Hz), 7.04 (d, 1H, J=7.5Hz), 7.23 (t, 2H, J=7.5 Hz), 7.36 (d, 2H, J=7.5 Hz), 7.57 (t, 111, J=8.4Hz), 8.07 (m, 1H). EI-MS: m/e 526 (M⁺), 94 (100%).

Example 203-{4-[2-Amino-6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 136-137° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 3.10 (d, 1H,J=13.5 Hz), 3.38 (d, 1H, J=13.5 Hz), 3.25 (q, 2H, J=13.5 Hz), 3.60 (t,4H, J=5.1 Hz), 3.81 (t, 4H, J=5.1 Hz), 5.35 (s, 1H), 6.60 (t, 1H, J=4.8Hz), 6.90 (d, 2H, J=7.5 Hz), 6.96 (t, 1H, J=6.6 Hz), 7.04 (m, 2H), 7.24(t, 2H, J=7.5 Hz), 7.36 (d, 2H, J=8.4 Hz), 8.33 (d, 2H, J=4.8 Hz);EI-MS: m/e 527 (M⁺), 94 (100%).

Example 213-{4-[2-Amino-6-(4-benzoyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Mp:117-119° C.

Example 223-{4-[2-Amino-6-(4-phenyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 150-151° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.36 (s, 3H), 3.10˜3.19 (m,5H), 3.37 (d, 1H, J=13.5 Hz), 3.54 (t, 4H, J=5.1 Hz), 5.29 (s, 1H), 6.83(t, 1H, J=7.2 Hz), 6.89˜6.99 (m, 5H), 7.02 (d, 2H, J=8.7 Hz), 7.21 (q,4H, J=7.8 Hz), 7.34 (d, 2H, J=8.1 Hz). EI-MS: m/e 525 (M⁺), 94 (100%).

Example 233-{4-{2-Amino-6-[4-(3-chloro-phenyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 212-214° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.35 (s, 3H), 3.15 (d, 1H,J=13.5 Hz), 3.20˜3.35 (m, 5H), 3.62 (t, 4H, J=5.1 Hz), 5.53 (s, 1H),6.83˜6.87 (m, 2H), 6.92 (m, 1H), 6.95˜7.03 (m, 4H), 7.24˜7.29 (m, 5H);EI-MS: m/e 559 (M⁺), 94 (100%).

Example 243-{4-{2-Amino-6-[4-(4-propyl-benzoyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Mp: 101-102° C.: ¹HNMR (300 MHz, d₆-DMSO): δ 0.88 (t, 3H, J=7.5 Hz),1.33 (s, 3H), 1.60 (q, 2H, J=7.5 Hz), 2.59 (t, 2H, J=7.5 Hz), 3.17 (d,1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.48˜3.55 (m, 8H), 5.50 (s,1H), 6.83 (d, 2H, J=8.1 Hz), 6.96˜7.00 (m, 3H), 7.23˜7.36 (m, 7H), 7.35(d, 1H, J=7.8 Hz); EI-MS: m/e 595 (M⁺), 94 (100%)

Example 253-{4-{2-Amino-6-[4-(2-methoxy-benzoyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Mp: 108-109° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.32 (s, 3H), 3.17 (d, 1H,J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.62 (m, 8H), 3.80 (s, 3H), 5.50(s, 1H), 6.83 (d, 2H, J=7.8 Hz), 6.93˜7.04 (m, 6H), 7.21˜7.25 (m, 4H),7.37 (m, 1H); EI-MS: m/e 583 (M⁺).

Example 263-{4-{2-Amino-6-[4-(3-cyano-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionic acid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Mp: 171-172° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.31 (s, 3H), 2.90 (t, 4H,J=5.1 Hz), 3.30 (m, 2H), 3.55 (t, 4H, J=5.1 Hz), 3.60 (s, 2H), 5.52 (s,1H), 6.84˜6.97 (m, 7H), 7.17˜7.23 (m, 6H).

Example 273-{4-[2-Amino-6-(4-cyclohexylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

mp 180-182° C.; ¹HNMR (300 MHz, CD₃OD): δ 0.94 (m, 2H), 1.27˜1.3 (m,4H), 1.35 (s, 3H), 1.69˜1.81 (m, 4H), 1.95 (s, 1H), 2.30 (d, 2H, J=6.9Hz), 2.56 (t, 4H, J=6.0 Hz), 3.13 (d, 1H, J=13.8 Hz), 3.39 (d, 1H,J=13.8 Hz), 3.52 (t, 4H, J=6.0 Hz), 5.27 (s, 1H), 6.89˜6.94 (m, 3H),6.98 (d, 2H, J=8.7 Hz), 7.19 (t, 2H, J=7.2 Hz), 7.33 (d, 2H, J=8.7 Hz);EI-MS: m/e 545 (M⁺), 94 (100%).

Example 283-{4-[6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the procedure of Example 2 toprovide a white solid.

mp 107-109° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.71 (t, 4H,J=5.1 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.64 (t,4H, J=5.1 Hz), 3.78 (s, 2H), 5.99 (s, 1H), 6.80˜6.91 (m, 3H), 7.01 (d,2H, J=8.7 Hz), 7.18 (d, 2H, J=7.5 Hz), 7.34˜7.37 (m, 7H), 8.15 (s, 1H);EI-MS: m/e 524 (M⁺), 159 (100%).

Example 293-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-(biphenyl-4-yloxy)-2-methyl-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.47 (t, 4H, J=5.7 Hz), 3.15 (d,1H, J=13.2 Hz), 3.40 (d, 1H, J=13.2 Hz), 3.50 (t, 4H, J=5.7 Hz), 3.57(s, 2H), 5.25 (s, 1H), 6.97-7.12 (d, d, 4H, J=5.7, 3.0 Hz), 7.22˜7.39(m, 10H), 7.45 (d, 2H, J=15.0 Hz), 7.32 (d, 2H, J=6.3 Hz). EI-MS: m/e615 (M⁺), 170 (100%).

Example 303-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-(4-methoxy-phenoxy)-2-methyl-propionicacid

¹HNMR (300 MHz, CD₃OD): δ 1.30 (s, 3H), 2.51 (t, 4H, J=5.1 Hz), 3.15 (d,1H, J=13.5 Hz), 3.40 (d, 1H, J=13.5 Hz), 3.50 (t, 4H, J=5.1 Hz), 3.60(s, 2H), 3.70 (s, 3H), 5.31 (s, 1H), 6.74 (d, 2H, J=9.3 Hz), 6.87 (d,2H, J=9.3 Hz), 6.99 (d, 2H, J=8.4 Hz), 7.29˜7.37 (m, 7H). EI-MS: m/e 569(M⁺), 124 (100%).

Example 313-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-p-tolyloxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

¹HNMR (300 MHz, CD₃OD): δ 1.33 (s, 3H), 2.23 (s, 3H), 2.71 (t, 4H, J=5.1Hz), 3.15 (d, 1H, J=13.5 Hz), 3.40 (d, 1H, J=13.5 Hz), 3.56 (t, 4H,J=5.1 Hz), 3.80 (s, 2H), 3.70 (s, 3H), 5.29 (s, 1H), 6.74 (d, 2H, J=9.3Hz), 6.87 (d, 2H, J=9.3 Hz), 6.99 (s, 2H, J=8.4 Hz), 7.29-7.37 (m, 7H).EI-MS: m/e 553 (M⁺), 107 (100%).

Example 323-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

¹HNMR (300 MHz, CD₃OD): δ 1.47 (s, 3H), 2.64 (t, 4H, J=5.1 Hz), 3.15 (d,1H, J=13.5 Hz), 3.55 (d, 1H, J=13.5 Hz), 3.50 (t, 4H, J=5.1 Hz), 3.60(s, 2H), 3.70 (s, 3H), 5.31 (s, 1H), 6.93 (d, 2H, J=8.4 Hz), 7.03 (d,2H, J=8.7 Hz), 7.29˜7.37 (m, 7H), 7.47 (d, 2H, J=8.4 Hz). EI-MS: m/e 607(M⁺), 161 (100%).

Example 333-{4-[6-(4-Benzyl-piperazin-1-yl)-2-phenyl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Example 343-{4-[6-(4-Benzyl-piperazin-1-yl)-2-methyl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Example 353-{4-[6-(4-Benzyl-piperazin-1-yl)-2-ethyl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 2.

Example 363-{4-[2-Amino-6-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The tile compound, shown above, was made as described below.

Step A3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester

3-[4-(2-Amino-6-chloro-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester and piperazine were reacted, as described in Example 2,Step G, to provide3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester, shown below, as a yellow oil.

Step B3-{4-[2-Amino-6-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester

To a stirring solution of3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester (1 mmol) in dry dichloromethane (20 ml) under N₂ wasadded pyridine-2-carbaldehyde (1.1 mmol). The reaction was stirred atroom temperature for half an hour, then Sodium triacetoxyborohydride(1.3 mmol) was then added and stirred over night. Water (10 mL), thebiphasic mixture was diluted with dichloromethane and partitioned, andthe organic layer was washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified in silica to provideyellow solid.

¹HNMR (300 MHz, CD₃OD): δ1.15 (t, 3H, J=7.2 Hz), 1.38 (s, 3H), 2.53 (t,4H, J=5.1 Hz), 3.15 (d, 1H, J=13.5 Hz), 3.37 (d, 1H, J=13.5 Hz), 3.51(t, 4H, J=5.1 Hz), 3.56 (s, 2H), 4.12 (q, 2H, J=7.2 Hz), 5.17 (s, 1H),6.63˜6.89 (m, 3H), 6.95 (d, 2H, J=8.4 Hz), 7.14 (t, 2H, J=8.1 Hz), 7.29(d, 2H, J=8.4 Hz), 7.32 (s, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.79 (t, d,J=8.1, 1.5 Hz), 8.46 (d, 1H, J=4.8 Hz).

Step C3-{4-[2-Amino-6-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the hydrolysis procedure ofExample 2, Step H, to provide a white solid.

mp 138-139° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.61 (t, 4H,J=5.1 Hz), 3.15 (d, 1H, J=13.5 Hz), 3.37 (d, 1H, J=13.5 Hz), 3.56 (t,4H, J=5.1 Hz), 3.71 (s, 2H), 5.22 (s, 1H), 6.68˜6.94 (m, 3H), 7.00 (d,2H, J=8.4 Hz), 7.19 (t, 2H, J=8.1 Hz), 7.34 (d, 2H, J=8.4 Hz), 7.37 (s,1H), 7.54 (d, 1H, J=8.1 Hz), 7.84 (t, d, J=8.1 Hz, J=1.5 Hz), 8.51 (d,1H, J=4.8 Hz). EI-MS: m/e 540 (M⁺), 94 (100%).

Example 373-{4-[2-Amino-6-(4-furan-2-ylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]phenyl}-2-methyl-2-phenoxy-propionic acid

This compound was prepared by means of a procedure similar to that usedfor Example 36.

mp 142-143° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.38 (s, 3H), 2.59 (t, 4H,J=5.1 Hz), 3.14 (d, 1H, J=13.8 Hz), 3.37 (d, 1H, J=13.8 Hz), 3.54 (t,4H, J=5.1 Hz), 3.71 (s, 2H), 5.26 (s, 1H), 6.38 (d, 2H, J=6.3 Hz), 6.78(t, 2H, J=5.7 Hz), 6.96 (s, 1H), 7.02 (d, 2H, J=8.7 Hz), 7.21 (t, 3H,J=6.3 Hz), 7.33 (d, 2H, J=8.7 Hz), 7.49 (s, 1H). EI-MS: m/e 529 (M⁺), 94(100%).

Example 383-{4-{2-Amino-6-[4-(4-nitro-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 36.

mp: 160-162° C.; ¹HNMR (300 MHz, d₆-DMSO): δ 1.36 (s, 3H), 2.39 (t, 4H,J=5.1 Hz), 3.13 (d, 1H, J=13.5 Hz), 3.39 (d, 1H, J=13.5 Hz), 3.56 (t,4H, J=5.1 Hz), 3.62 (s, 2H), 5.46 (s, 1H), 6.77 (d, 2H, J=7.8 Hz), 6.99(d, 2H, J=7.8 Hz), 6.78 (t, 2H, J=8.4 Hz), 7.20˜7.28 (m, 5H), 7.60 (d,2H, J=8.4 Hz), 8.18 (d, 2H, J=8.4 Hz); EI-MS: m/e 584 (M⁺).

Example 393-{4-[2-Amino-6-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionic acid

This compound was prepared by means of a procedure similar to that usedfor Example 36.

Mp: 141-143° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.39 (s, 3H), 2.46 (t, 4H,J=5.1 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.50 (t,4H, J=5.1 Hz), 3.65 (s, 2H), 5.22 (s, 1H), 6.87˜6.94 (m, 3H), 7.01 (d,2H, J=11.1 Hz), 7.20 (t, 2H, J=8.4 Hz), 7.32 (d, 2H, J=11.1 Hz), 7.42(m, 1H), 7.87 (m, 1H), 8.51 (m, 2H); EI-MS: m/e 540 (M⁺).

Example 403-{4-[2-Amino-6-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 36.

Mp: 137-138° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.39 (s, 3H), 2.48 (t, 4H,J=5.7 Hz), 3.20 (d, 1H, J=13.5 Hz), 3.38 (d, 1H, J=13.5 Hz), 3.52 (t,4H, J=5.7 Hz), 3.62 (s, 2H), 5.25 (s, 1H), 6.86˜6.95 (m, 3H), 7.02 (d,2H, J=8.7 Hz), 7.20 (t, 2H, J=6.3 Hz), 7.34 (d, 2H, J=8.7 Hz), 7.46 (d,2H, J=6.0 Hz), 8.48 (d, 2H, J=6.0 Hz); EI-MS: m/e 540 (M⁺).

Example 413-{4-{2-Amino-6-[4-(2-iodo-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 36.

Example 423-{4-{2-Amino-6-[4-(2-methoxy-benzyl)-piperazin-1-yl]-pyrimidin-4-yloxy}-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 36.

Example 433-{4-[6-(4-Benzyl-piperazin-1-yl)-2-phenoxy-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The tile compound, shown above, was made as described below.

Step A 4,6-Dichloro-2-phenoxy-pyrimidine

Phenol (0.94 g, 10 mmol) and sodium hydroxide (0.44 g, 11 mmol) in water(20 ml) were added to 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) inacetone (20 ml) at 0° C. The mixture was stirred over night. Theprecipitate then filtered through celite, then the most of the acetonewas removed in vacuo. The resulting aqueous solution was extracted withethyl acetate, dried over sodium sulfate, and concentrated in vacuo. Theresidue was purified in silica to provide a colorless oil.

Step B 4-(4-Benzyl-piperazin-1-yl)-6-chloro-2-phenoxy-pyrimidine

The title compound was the prepared using the hydrolysis procedure ofExample 2, Step F, to provide a white solid.

¹HNMR (300 MHz, CDCl₃): δ 2.48 (t, 4H, J=8.1 Hz), 3.53˜3.58 (m, 6H),5.67 (s, 1H), 7.10˜7.39 (m, 10H).

Step C3-{4-[6-(4-Benzyl-piperazin-1-yl)-2-phenoxy-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester

The title compound was the prepared using the hydrolysis procedure ofExample 2, Step F, to provide a white solid.

¹HNMR (300 MHz, d₆-DMSO): δ 1.10 (t, 3H, J=7.2 Hz), 1.33 (s, 3H), 2.23(t, 4H, J=5.1 Hz), 3.13 (d, 1H, J=13.8 Hz), 3.39 (d, 1H, J=13.8 Hz),3.17 (q, 2H, J=13.5 Hz), 3.40 (t, 4H, J=5.1 Hz), 3.42 (s, 2H), 4.10 (q,2H, J=7.2 Hz), 5.36 (s, 1H), 6.73 (d, 2H, J=7.8 Hz), 6.92 (m, 1H), 7.07(d, 2H), 7.14 (d, 2H, J=7.8 Hz), 7.18˜7.30 (m, 9H), 7.39 (t, 3H, J=7.8Hz).

Step D3-{4-[6-(4-Benzyl-piperazin-1-yl)-2-phenoxy-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the hydrolysis procedure ofExample 2, Step H, to provide a white solid.

Mp: 126-128° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.35 (s, 3H), 2.94 (t, 4H,J=5.1 Hz), 3.20 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.67 (t,4H, J=5.1 Hz), 4.01 (s, 2H), 5.54 (s, 1H), 6.87 (d, 2H, J=8.7 Hz), 6.94(t, 1H, J=7.2 Hz), 7.01 (d, 2H, J=7.2 Hz), 7.11 (d, 2H, J=8.1 Hz), 7.21(t, 3H, J=7.5 Hz), 7.31˜7.38 (m, 4H), 7.40 (s, 5H); EI-MS: m/e 616 (M⁺).

Example 443-{4-[2-(4-Benzyl-piperazin-1-yl)-6-phenoxy-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the procedure of Example 43 toprovide a white solid.

mp: 135-137° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.30 (s, 3H), 2.54 (t, 4H,J=5.1 Hz), 3.18 (q, 2H, J=13.5 Hz), 3.44 (t, 4H, J=5.1 Hz), 3.65 (s,2H), 5.69 (s, 1H), 6.85-6.91 (m, 3H), 7.01 (d, 2H, J=7.8 Hz), 7.10 (d,2H, J=9.0 Hz), 7.18 (t, 3H, J=8.1 Hz), 7.23-7.41 (m, 9H); EI-MS: m/e 616(M⁺).

Example 453-{4-[6-(4-Benzyl-piperazin-1-yl)-2-methoxy-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the procedure of Example 43 toprovide a white solid.

Example 463-{4-[6-(4-Benzyl-piperazin-1-yl)-2-ethoxy-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the procedure of Example 43 toprovide a white solid.

Example 473-{4-[2-Benzylamino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The tile compound, shown above, was made as described below.

Step A Benzyl-(4,6-dichloro-pyrimidin-2-yl)-amine

Benzylamine (0.53 g, 0.54 ml, 5 mmol) and triethylamine (0.50 g, 0.69ml, 5 mmol) in tetrahydrofuran (20 ml) were added to2,4,6-trichloropyrimidine (0.917 g, 5 mmol) in tetrahydrofuran (20 ml)at 0° C. The mixture was stirred for several hours. The precipitate thenfiltered through celite, then the most of the methanol was removed invacuo. The residue was purified in silica to provide a colorless oil.

¹HNMR (300 MHz, CDCl₃): δ 4.63 (d, 2H, J=5.7 Hz), 6.64 (s, 1H),7.27˜7.39 (m, 5H).

Step B3-[4-(2-Benzylamino-6-chloro-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester

3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (60 mg,0.2 mmol), benzyl-(4,6-dichloro-pyrimidin-2-yl)-amine (50 mg, 0.2 mmol)and Cs₂CO₃ (76 mg, 0.22 mmol) were combined in anhydrousN,N-dimethylformamide (DMF) (5 mL) and stirred at 90° C. in dryatmosphere for 5 h. The DMF was removed in vacuo, the residue waspurified in silica to provide a white oil.

Step C

3-{4-[2-Benzylamino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid ethyl ester

3-[4-(2-Benzylamino-6-chloro-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionicacid ethyl ester (60 mg, 0.1 mmol), 1-Benzyl-piperazine (25 mg, 0.25 ml,0.15 mmol) and Cs₂CO₃ (35 mg, 0.11 mmol) were combined in anhydrousN,N-dimethylformamide (DMF) (5 mL) and stirred at 90° C. in dryatmosphere overnight. The DMF was removed in vacuo, the residue waspurified in silica to provide a white oil.

Step D3-{4-[2-Benzylamino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound was the prepared using the hydrolysis procedure ofExample 2, Step H, to provide a white solid.

mp 104-106° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.36 (s, 3H), 2.73 (t, 4H,J=4.8 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.35 (d, 1H, J=13.5 Hz), 3.36˜3.50(m, 6H), 4.41 (s, 2H), 5.24 (s, 1H), 6.88˜7.04 (m, 5H), 7.16˜7.32 (m,9H), 7.38˜7.41 (m, 5H), EI-MS: m/e 629 (M⁺), 94 (100%).

Example 483-{4-[6-(4-Benzyl-piperazin-1-yl)-2-methylamino-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

Example 493-{4-[6-(4-Benzyl-piperazin-1-yl)-2-dimethylamino-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

mp 136-138° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.37 (s, 3H), 2.82 (t, 4H,J=5.7 Hz), 3.00 (s, 6H), 3.19 (d, 1H, J=13.5 Hz), 3.32 (d, 1H, J=13.5Hz), 3.61 (t, 4H, J=5.7 Hz), 3.93 (s, 2H), 5.11 (s, 1H), 6.87˜6.92 (m,3H), 7.01 (d, 2H, J=8.1 Hz), 7.20 (t, 2H, J=8.1 Hz), 7.31 (d, 2H, J=8.7Hz), 7.37˜7.43 (m, 5H), EI-MS: m/e 567 (M⁺), 107 (100%).

Example 503-{4-[6-(4-Benzyl-piperazin-1-yl)-2-ethylamino-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

mp 106-107° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.09 (t, 3H, J=7.2 Hz), 1.40(s, 3H), 3.00 (t, 4H, J=5.7 Hz), 3.13 (d, 1H, J=13.5 Hz), 3.30˜3.35 (m,3H), 3.72 (t, 4H, J=5.7 Hz), 4.01 (s, 1H), 5.18 (s, 1H), 6.82˜6.96 (m,3H), 7.02 (d, 2H, J=8.7 Hz), 7.21 (t, 2H, J=8.7 Hz), 7.31 (d, 2H, J=8.4Hz), 7.18˜7.23 (m, 5H), EI-MS: m/e 567 (M⁺), 107 (100%).

Example 513-{4-[6-(4-Benzyl-piperazin-1-yl)-2-diethylamino-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

mp 120-121° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.03 (t, 6H, J=7.2 Hz), 1.35(s, 3H), 2.82 (t, 4H, J=5.7 Hz), 3.17 (d, 1H, J=13.5 Hz), 3.32 (d, 1H,J=13.5 Hz), 3.42 (d, 4H, J=7.2 Hz), 3.61 (t, 4H, J=5.7 Hz), 3.88 (s,2H), 5.13 (s, 1H), 6.88˜6.94 (m, 3H), 6.96 (d, 2H, J=8.4 Hz), 7.19 (t,2H, J=8.1 Hz), 7.30 (d, 2H, J=8.7 Hz), 7.36˜7.41 (m, 5H); EI-MS: m/e 595(M⁺), 94 (100%).

Example 523-{4-[6-(4-Benzyl-piperazin-1-yl)-2-piperidin-1-yl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

mp 125-126° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.32 (s, 3H), 1.47 (m, 4H),1.61 (m, 2H), 2.60 (t, 4H J=5.7 Hz), 3.15 (d, 1H, J=13.5 Hz), 3.33 (d,1H, J=13.5 Hz), 3.54 (m, 4H), 3.59 (m, 4H), 3.70 (s, 2H), 5.11 (s, 1H),6.88-6.91 (m, 3H), 6.98 (d, 2H, J=7.8 Hz), 7.17 (t, 2H, J=7.5 Hz), 7.31(d, 2H, J=8.4 Hz), 7.35˜7.48 (m, 5H); EI-MS: m/e 607 (M⁺), 94 (100%).

Example 533-{4-[6-(4-Benzyl-piperazin-1-yl)-2-morpholin-4-yl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

mp 127-129° C.; ¹HNMR (300 MHz, CD₃OD): δ1.38 (s, 3H), 2.78 (t, 4H,J=5.7 Hz), 3.15 (d, 1H, J=13.8 Hz), 3.33 (d, 1H, J=13.8 Hz), 3.52˜3.60(m, 12H), 3.89 (s, 2H), 5.29 (s, 1H), 6.82˜6.96 (m, 3H), 7.06 (d, 2H,J=8.7 Hz), 7.20 (t, 2H, J=8.7 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.18˜7.23 (m,5H); EI-MS: m/e 609 (M⁺), 94 (100%).

Example 543-{4-[6-(4-Benzyl-piperazin-1-yl)-2-pyrrolidin-1-yl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

mp 126-127° C.; ¹HNMR (300 MHz, CD₃OD): δ 1.40 (s, 3H), 1.91 (m, 4H),2.78 (m, 4H), 3.15 (d, 1H, J=13.5 Hz), 3.33 (d, 1H, J=13.5 Hz), 3.41 (m,4H), 3.62 (m, 4H), 3.87 (s, 2H), 5.09 (s, 1H), 6.87˜6.93 (m, 3H), 7.02(d, 211, J=8.4 Hz), 7.18 (t, 2H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz),7.37˜7.41 (m, 5H); EI-MS: m/e 593 (M⁺), 94 (100%).

Example 553-{4-[2-phenylamino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

Example 563-{4-[6-(4-Benzyl-piperazin-1-yl)-2-piperazin-1-yl-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

Example 573-{4-[2,6-Bis-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

This compound was prepared by means of a procedure similar to that usedfor Example 47.

The substituents in the compounds of Examples are listed in thefollowing Tables:

Example Compound Substituent Groups No. No. R₂ R₄ R₅ R₆ R₁₀ R₁₁ R₁₂ 1 1NH₂ H C₂H₅ H H H H 2 2 NH₂ CH₃ Ph H H H H 3 3 NH₂ CH₃ Ph H H H H 4 4 NH₂CH₃ Ph H H H H 7 7 NH₂ CH₃ Ph H H H F 8 8 NH₂ CH₃ Ph H H H CF₃ 9 9 NH₂CH₃ Ph H H CH₃ H 10 10 NH₂ CH₃ Ph H H CF₃ H 11 11 NH₂ CH₃ Ph H H Cl H 1212 NH₂ CH₃ Ph H H F H 13 13 NH₂ CH₃ Ph H H H Cl 14 14 NH₂ CH₃ Ph H H H(CH₃)₃ 15 15 NH₂ CH₃ Ph H H H Br 16 16 NH₂ CH₃ Ph H H Br H 17 17 NH₂ CH₃Ph H H OPh H 26 26 NH₂ CH₃ Ph H H CN H 28 28 H CH₃ Ph H H H H 29 29 NH₂CH₃ Biphenyl H H H H 30 30 NH₂ CH₃ 4-OCH₃-Ph H H H H 31 31 NH₂ CH₃4-CH₃-Ph H H H H 32 32 NH₂ CH₃ 4-CF₃-Ph H H H H 33 33 Ph CH₃ Ph H H H H34 34 CH₃ CH₃ Ph H H H H 35 35 NH₂ CH₃ Ph H H H H 38 38 NH₂ CH₃ Ph H H HNO₂ 41 41 NH₂ CH₃ Ph H I H H 42 42 NH₂ CH₃ Ph H OCH₃ H H 43 43 OPh CH₃Ph H H H H 45 45 OCH₃ CH₃ Ph H H H H 46 46 OC₂H₅ CH₃ Ph H H H H 47 47NHBn CH₃ Ph H H H H 48 48 NHCH₃ CH₃ Ph H H H H 49 49 N(CH₃)₂ CH₃ Ph H HH H 50 50 NHC₂H₅ CH₃ Ph H H H H 51 51 N(C₂H₅)₂ CH₃ Ph H H H H 52 52piperidinyl CH₃ Ph H H H H 53 53 morpholinyl CH₃ Ph H H H H 54 54pyrrolidinyl CH₃ Ph H H H H 55 55 NHPh CH₃ Ph H H H H 56 56 piperazinylCH₃ Ph H H H H 57 57 4-benzyl-piperazin- CH₃ Ph H H H H 1-yl

Example Compound Substituent Groups No. No. R₂ R₄ R₅ R₆ R₈  5  5 NH2 CH3Ph H

 6  6 NH2 CH3 Ph H

18 18 NH2 CH3 Ph H

19 19 NH2 CH3 Ph H

20 20 NH2 CH3 Ph H

21 21 NH2 CH3 Ph H

22 22 NH2 CH3 Ph H

23 23 NH2 CH3 Ph H

24 24 NH2 CH3 Ph H

25 25 NH2 CH3 Ph H

27 27 NH2 CH3 Ph H

36 36 NH2 CH3 Ph H

37 37 NH2 CH3 Ph H

39 39 NH2 CH3 Ph H

40 40 NH2 CH3 Ph H

44 44

CH₃ Ph H

Example 58 Transient Transfection and Transcription Assay

cDNAs for Human RXR, PPAR were obtained by RTPCR from the human liver oradipose tissues. Amplified cDNAs were cloned into pcDNA3.1 expressionvector and the inserts were confirmed by sequencing. U2OS cells werecultured in McCoy's 5A with 10% heat-inactivated fetal bovine serum in ahumidified 5% CO₂ atmosphere at 37° C. Cells were seeded in 96-wellplates the day before transfection to give a confluence of 50-80% attransfection. A total of 60 ng of DNA containing 10 ng of hRXR, 10 ng ofpCMV Gal, 10 ng of nuclear receptor expression vectors and 30 ng of thecorresponding reporters were cotransfected per well using FuGene6transfection reagent according to the manufacturer's instructions.Following 24 h after transfection, cells were incubated with 10%charcoal-stripped FBS DMEM and were treated with the individual compounddissolved in DMSO. The final concentration of DMSO in culture medium was0.1%. Cells were treated with compound for 24 h, and then collected withCell Culture Lysis buffer. Luciferase activity was monitored using theluciferase assay kit according to the manufacturers instructions. Lightemission was read in a Labsystems Ascent Fluoroskan reader. To measuregalactosidase activity to normalize the luciferase data, 50 IL ofsupernatant from each transfection lysate was transferred to a newmicroplate. Galactosidase assays were performed in the microwell platesusing a kit from Promega and read in a microplate reader. Compounds weretested in five concentrations ranging from 0.01 to 10 μM. Cells weretreated with compound for 24 h followed by luciferase assay. EC₅₀ valueswere calculated via nonlinear regression using GraphPad PRISM 3.02(GraphPad Software, San Diego, Calif.). The results were expressed asmeans (SD).

TABLE 1 No EC₅₀ (μM) 2 6.76 3 3.31 4 5.75 5 6.46 6 3.39 9 4.17 10 4.2711 5.13 12 6.46 14 6.03 15 5.89 16 6.31 18 6.46 19 6.31 20 5.89 22 4.6823 4.37 27 5.37 28 4.68 29 2.57 30 5.75 31 3.80 32 2.24 37 3.89 43 1.6244 4.68 47 6.31 49 2.95 50 6.03 51 7.08 52 4.68 53 3.98 54 3.80

Example 59 The Effect of Compound 2 in the Han:Sprd Rat Model of Adpkd

We examined the renal protection, potential side effects of compound 2and its effect on life span in the Han:SPRD rat model of ADPKD.

1. Animals and Materials

Han: SPRD rats were obtained from our own breeding colony that isderived from animals that were kindly provided to us by Mayo Clinic(Rochester Minn.), All animal procedures and care were taken at theSPF-level Laboratory Animal Center of the Second Military MedicalUniversity (Shanghai, Calif.). Carboxymethyl cellulose sodium (CMC-Na)was purchased from Shanghai Chemical Reagent Company. Automatic clinicalchemistry analyzer (Hitachi Clinical Analyzer 7080).

2. Methods

2.1 Experimental protocol: A total of 48 Han:SPRD rats (about ⅔ ratswere Cy/+, ⅓ were +/+, homozygote rats −/− die within 3 weeks), all at 3weeks of age, were randomized into 2 groups: negative control group andtreatment groups (10 mg/kg.d compound 2). The rats of negative controlgroup were given 1% CMC-Na, while the rats of treatment group were given10 mg/kg.d compound 2 (suspended in 1% CMC-Na) by daily gavage from 3weeks through 11 weeks of age, removal +/+rats in both groups, thengeneral animal feeds were given to rats in control group, the rats oftreatment group were given animal feeds added by 0.03% of compound 2(approximately 10 mg/kg. d), both groups were maintained with freeaccess to water. Long-term observation of the rats until they died,record the length of their life span.2.2 Physiological and biochemical indexes: since the day of treatment,general state and body weight of rats were examined and recorded everymonth, Blood (2 ml) was obtained from the rat orbital venous plexususing a glass capillary tube, then centrifuged for 10 minutes at 4000rpm to collect serum for biochemical analysis including blood ureanitrogen (BUN), ALT, AST, serum lipids et. Urine was collected usingMetabolic Cage for 24-hour urine protein analysis.

3. Results

3.1 Blood urea nitrogen (BUN): After 2 months of treatment, the averageBUN level was lower in the treatment group compared with control group(P<0.001), indicating that compound 2 treatment delayed the progressionof renal failure.

TABLE 2 Blood urea nitrogen (BUN) levels Blood urea nitrogen (BUN)levels (mmol/L) Intervention time Negative Control Group Treatment Groupbaseline  4.79 ± 0.66 4.97 ± 0.67  1 month 11.54 ± 0.81 11.55 ± 0.57   2month 13.80 ± 1.63 12.36 ± 0.77*  3 month 15.07 ± 1.60 12.58 ± 1.35**  4month 15.44 ± 0.90 12.79 ± 1.41*** 5 month 15.55 ± 1.11 13.10 ± 1.64***6 month 16.34 ± 1.47 13.26 ± 1.05*** 7 month 17.32 ± 1.02 12.60 ±1.40*** 8 month 18.62 ± 1.93 13.16 ± 1.73*** 9 month 21.97 ± 2.94 12.87± 2.72*** 10 month  27.87 ± 1.36 13.17 ± 3.70*** *P < 0.05; **P < 0.013.2 24-hour urine protein: After 2 months of treatment, the average24-hour urine protein level was lower in the treatment group comparedwith the negative control group (P<0.001), revealing a significant renalprotection after the use of the compound 2.

TABLE 3 24-hour urine protein level 24-hour urine protein level (mg/24h) Intervention time Negative Control Group Treatment Group baselineNon-detected Non-detected 1 month 65.0 ± 3.1 62.3 ± 6.3   2 month 73.9 ±8.9 64.1 ± 5.0*  3 month  69.8 ± 25.6 67.1 ± 4.9   4 month  80.5 ± 11.166.3 ± 4.6*** 5 month 75.4 ± 8.0 67.1 ± 3.6*  6 month 80.3 ± 9.3 66.0 ±8.6**  7 month 80.0 ± 9.1 64.4 ± 2.8*** 8 month 82.6 ± 6.1 70.4 ± 8.8** 9 month 88.3 ± 7.0 67.8 ± 3.2*** 10 month   88.1 ± 10.9 70.0 ± 5.9*** *P< 0.05; **P < 0.013.3 Comparison of long-term survival: The average survival time of thecontrol group is 389.3 days; the average survival time of treatmentgroup is 451.1+ days with 2 rats still alive. Detail in Attached Table.3.4 after compound 2 treatment, no statistically significant change inbody weight was noted, the values of serum ALT, AST and serum lipidswere still within the normal range.

The result of the above experiments clearly indicates that compound 2,at suitable dose, can delay the progression of renal failure, attenuatealbuminuria, prolong the life span of Han:SPRD rats without any obviouspoisonous and side effects during the intervention time (See FIG. 1).

Example 60 Anticancer Effects of Peroxisome Proliferator-ActivatedReceptor γ Agonists

The growth inhibition was evaluated by the modified MTT assay. Briefly,the cells were seeded at 1×104 cells/well in 96-well plates (Falcon,Calif., USA), and incubated for 24 h in 100 mL culture media with 10%FCS. The media were then replaced by serum-free medium. After 24 h, themedia were placed in triplicate with grade concentrations of compounds.As controls, the cells were cultivated in DMEM/F12 only. The cells werethen treated by MTT (Sigma, USA) assay, 10 mL (5 g/L) for 4 h. After theremoval of the supernatant, the purple-blue sediment was dissolved in100 μL/well DMSO, and the optical densities were read on the multi-wellscanning spectrophotometer (Labsystems Dragon, Finland) at 492 nm(A492). The growth inhibition rate (GIR) of the treated cells wascalculated using Equation:

GIR(%)={1−[A490/A490(control)]}×100%

The results were also converted to IC50 (the compound concentrationrequired for 50% growth inhibition of tumor cells), which werecalculated by using the sigmoidal fitting model by the Origin 7.0software (OriginLab, Northampton, Mass., USA). The mean IC50 wasdetermined from the results of 3 independent tests.

TABLE 4 IC50 Compound SPC-A1 T24 HepG2 MCF-7 Rosiglitazone 59.8 μM 69.0μM 80.2 μM 45.6 μM 2 65.5 μM 72.0 μM 80.6 μM 55.0 μM 5  >50 μM >50μM >50 μM  >50 μM 6 49.8 μM 36.3 μM 24.8 μM 42.2 μM 7  >50 μM >50 μM >50μM  >50 μM 8 42.5 μM 36.2 μM >50 μM 28.5 μM 9 48.9 μM >50 μM >50 μM 38.0μM 10 25.1 μM 29.1 μM 38.1 μM 15.1 μM 11 47.6 μM >50 μM >50 μM 40.6 μM12  >50 μM >50 μM >50 μM  >50 μM 13  >50 μM 45.6 μM >50 μM 48.9 μM 14 8.6 μM 12.5 μM 26.5 μM  7.9 μM 15 45.3 μM >50 μM >50 μM 42.2 μM 16 37.0μM 41.0 μM 48.0 μM 30.0 μM 18  >50 μM >50 μM >50 μM  >50 μM 19 42.5 μM30.8.5 μM 49.5 μM  >50 μM 20 29.1 μM 20.1 μM 32.6 μM 35.7 μM 21  >50μM >50 μM >50 μM  >50 μM 22 32.5 μM 22.6 μM 29.7 μM 15.5.6 μM   23 12.0μM 15.2 μM 20.0 μM 11.8 μM 24 43.7 μM 39.4 μM >50 μM 38.2 μM 25  >50μM >50 μM >50 μM  >50 μM 26 37.7 μM 38.8 μM 35.6 μM 23.3 μM 27  >50μM >50 μM 44.5 μM  >50 μM 28 28.6 μM 19.6 μM 29.3 μM 14.6 μM 29 34.1 μM40.0 μM >50 μM  >50 μM 30 38.9 μM >50 μM >50 μM 42.8 μM 31 35.3 μM 40.8μM 45.5 μM 29.3 μM 32 28.0 μM 37.7 μM 30.0 μM 34.2 μM 36  >50 μM >50μM >50 μM  >50 μM 37 37.6 μM 40.6 μM >50 μM 47.6 μM 38  >50 μM 40.3μM >50 μM 45.3 μM 39 43.5 μM >50 μM >50 μM 38.8 μM 40 46.5 μM >50 μM >50μM 45.2 μM 43 32.5 μM >50 μM >50 μM 33.5 μM 44 14.1 μM 11.1 μM 35.2 μM15.4 μM 47 31.5 μM >50 μM >50 μM 22.8 μM 49  >50 μM >50 μM >50 μM  >50μM 50 46.6 μM >50 μM >50 μM 33.7 μM 51 36.6 μM 21.9 μM 37.5 μM 27.6 μM52  7.8 μM 12.4 μM 17.9 μM 17.6 μM 53 22.4 μM 15.8 μM 22.2 μM 12.5 μM 54 >50 μM >50 μM >50 μM  >50 μM

The results indicate that most of the synthesized compounds demonstratedmoderate anti-proliferatory effects on SPC-A1, T24, HepG2, MCF-7 celllines, especially some of them showed inhibitory capabilityapproximately several times higher than that of the rosiglitazone.

1. A compound represented by Structural Formula I, pharmaceuticallyacceptable salts, solvates, or hydrates thereof:

wherein: X is CH₂, CH(OH), C(O)O, NH, S, or SO₂; Y is an unsubstitutedor substituted phenyl, wherein the substituted phenyl is substituted byone or more of the following groups: C₁-C₆ straight-chain orbranched-chain alkyl, halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, and trifluoromethoxy; n is 0, 2, 3, or4; R₁ is a hydro, or C₁-C₆ alkyl, C₁-C₈ alkoxyl, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, phenoxy, unsubstitutedC₃-C₆ heterocycloalkyl or substituted C₃-C₆ heterocycloalkyl, whereinthe substituted C₃-C₆ heterocycloalkyl is substituted by one or more ofthe following groups: C₁-C₈ alkyl, halogen, C₃-C₆ cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy; unsubstituted orsubstituted C₆-C₁₂ heteroaryl containing one or two oxygen or nitrogen,unsubstituted or substituted C₃-C₆ heterocycloalkyl containing one ortwo oxygen or nitrogen, unsubstituted or substituted(C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing one or two oxygen ornitrogen, unsubstituted or substituted phenyl, unsubstituted orsubstituted (C₅-C₁₂)aryl(C₁-C₆)alkyl (such as: benzyl, phenethyl,naphthalen-1-ylmethyl), unsubstituted or substituted phenoxy, andunsubstituted or substituted carbobenzoxy, wherein the substitutedgroups are independently substituted by one or more of the followinggroups: halogen, oxo, C₁-C₆ alkyl, C₁-C₈ alkoxyl, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy; and unsubstituted or substituted phenyl or phenoxy,wherein the subtituted phenyl or phenoxy is independently substituted byone or more substituents selected from: halogen, C₁-C₆ haloalkyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, and trifluoromethoxy;R₂ is H, phenyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, or unsubstituted orsubstituted amino, wherein the substituted groups are independentlysubstituted by one or more of the following groups: C₁-C₆ alkyl, C₃-C₇carbocyclyl, phenyl, benzyl, aralkyl, sulfanilamino, pyridyl, C₁-C₄acyl); unsubstituted or substituted C₃-C₆ heterocycloalkyl containingone or two oxygen or nitrogen, and unsubstituted or substituted phenoxy,wherein the substituted amino group is substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, and benzyl; R₃ is H,C₁-C₈ alkoxyl, halogen, mercapto, cyano, nitro, hydroxyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ straight-chain orbranched-chain alkyl, phenyl, aralkyl, thioureido, or unsubstituted orsubstituted amino, wherein the substituted amino group is substituted byone or more of the following groups: C₁-C₆ straight-chain orbranched-chain alkyl, C₃-C₆ heterocycloalkyl, phenyl, aralkyl,sulfanilamino, pyridyl, and C₁-C₄ acyl; R₄ is H, C₁-C₆ straight-chain orbranched-chain alkyl, C₁-C₈ alkoxyl, mercapto, hydroxyl,trifluoromethyl, trifluoromethoxy, or unsubstituted or substitutedphenoxy, wherein the substituted phenoxy is substituted by one or moreof the following groups: halogen, C₁-C₆ haloalkyl, amino, mercapto,hydroxyl, trifluoromethyl, and trifluoromethoxy; R₅ is H, C₁-C₆straight-chain or branched-chain alkyl, or unsubstituted or substitutedphenyl, wherein the substituted phenoxy is substituted by one or more ofthe following groups: halogen, C₁-C₆ haloalkyl, C₁-C₆ straight-chain orbranched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano, hydroxyl,trifluoromethyl, trifluoromethoxy, and unsubstituted or substitutedphenyl, wherein the substituted phenoxy group is substituted by one ormore of the following groups: halogen, C₁-C₄ haloalkyl, amino, mercapto,hydroxyl, trifluoromethyl, and trifluoromethoxy; R₆ is H, C₁-C₆straight-chain or branched-chain alkyl.
 2. The compound,pharmaceutically acceptable salts, solvates, or hydrates thereof ofclaim 1, wherein the compound has a structure represented by StructuralFormula II:

wherein: R₁, R₂, R₃, R₄, R₅ and R₆ is as defined for Structural FormulaI; R₇ are each, independently, H, C₁-C₆ straight-chain or branched-chainalkyl, halo, C₁-C₆ haloalkyl, amino, mercapto, cyano, nitro, hydroxyl,trifluoromethyl, or trifluoromethoxy.
 3. The compound, pharmaceuticallyacceptable salts, solvates, or hydrates thereof of claim 2, wherein thecompound has a structure represented by Structural Formula III:

wherein: R₂, R₃, R₄, R₅, R₆ and R₇ are as defined for Structural FormulaII; R₈ are each, independently, H, C₁-C₆ straight-chain orbranched-chain alkyl, C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl; unsubstitutedor substituted C₆-C₁₂ heteroaryl containing one or two oxygen ornitrogen, unsubstituted or substituted C₃-C₆ heterocycloalkyl containingone or two oxygen or nitrogen, unsubstituted or substituted(C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing one or two oxygen ornitrogen, unsubstituted or substituted phenyl, unsubstituted orsubstituted (C₅-C₁₂)aryl(C₁-C₆)alkyl (such as: benzyl, phenethyl,naphthalen-1-ylmethyl), unsubstituted or substituted phenoxy,unsubstituted or substituted carbobenzoxy, wherein the substitutedgroups are independently substituted by one or more of the followinggroups: halogen, C₁-C₆ haloalkyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy,unsubstituted or substituted phenyl or phenoxy, wherein the substitutedphenyl or phenoxy is independently substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,hydroxyl, trifluoromethyl, and trifluoromethoxy; R₉ is H, C₁-C₈straight-chain or branched-chain alkyl, halogen, C₁-C₄ haloalkyl, amino,mercapto, cyano, hydroxyl, trifluoromethyl, or trifluoromethoxy.
 4. Thecompound, pharmaceutically acceptable salts, solvates, or hydratesthereof of claim 3, wherein the compound has a structure represented byStructural Formula IV:

wherein: R₂, R₃, R₄, R₆, R₇ and R₉ are as defined for Structural FormulaIII; R₁₀, R₁₁, and R₁₂ are H, halogen, C₁-C₆ haloalkyl, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto,cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstitutedor substituted phenyl or phenoxy, wherein the substituted phenyl orphenoxy is independently substituted by one or more of the followinggroups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano, hydroxyl,trifluoromethyl, and trifluoromethoxy; R₁₃, R₁₄, and R₁₅ areindependently halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,hydroxyl, trifluoromethyl, trifluoromethoxy, and unsubstituted orsubstituted phenyl, wherein the substituted phenyl is substituted by oneor more of the following groups: halogen, C₁-C₆ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy.
 5. Thecompound, pharmaceutically acceptable salts, solvates, or hydratesthereof of claim 4, wherein the compound has a structure represented byStructural Formula V:

wherein: R₃, R₄, R₆, R₇, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are asdefined for Structural Formula IV; R₁₆ optionally and independentlysubstituted one or two times with C₁-C₆ straight-chain or branched-chainalkyl, C₃-C₇ cycloalkyl, phenyl, aralkyl, sulfanilamino, pyridyl, C₁-C₄acyl; unsubstituted or substituted C₃-C₆ heterocycloalkyl, wherein thesubstituted C₃-C₆ heterocycloalkyl is substituted by one or more of thefollowing groups: halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,hydroxyl, trifluoromethyl, and trifluoromethoxy.
 6. A process forpreparing a compound represented by Structural Formula I, orpharmaceutically acceptable salts, solvates, or hydrates thereof, whichcomprises the step of: treating compound (Ia), in the presence of cesiumcarbonate, with compound (Ib) in a polar solvent at a temperature ofabout 60° C. to about 100° C. to form compound (I) to cause the reaction(1):

wherein: X is CH₁, CH(OH), C(O)O, NH, S, or SO₂; Y is an unsubstitutedor substituted phenyl, wherein the substituted phenyl is substituted byone or more of the following groups: C₁-C₆ straight-chain orbranched-chain alkyl, halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, and trifluoromethoxy; n is 0, 2, 3, or4; R₁ is a hydro, or C₁-C₆ alkyl, C₁-C₈ alkoxyl, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, phenoxy, unsubstitutedC₃-C₆ heterocycloalkyl or substituted C₃-C₆ heterocycloalkyl, whereinthe substituted C₃-C₆ heterocycloalkyl is substituted by one or more ofthe following groups: C₁-C₈ alkyl, halogen, C₃-C₆ cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy; unsubstituted orsubstituted C₆-C₁₂ heteroaryl containing one or two oxygen or nitrogen,unsubstituted or substituted C₃-C₆ heterocycloalkyl containing one ortwo oxygen or nitrogen, unsubstituted or substituted(C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing one or two oxygen ornitrogen, unsubstituted or substituted phenyl, unsubstituted orsubstituted (C₅-C₁₂)aryl(C₁-C₆)alkyl (such as: benzyl, phenethyl,naphthalen-1-ylmethyl), unsubstituted or substituted phenoxy, andunsubstituted or substituted carbobenzoxy, wherein the substitutedgroups are independently substituted by one or more of the followinggroups: halogen, oxo, C₁-C₆ alkyl, C₁-C₈ alkoxyl, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy; and unsubstituted or substituted phenyl or phenoxy,wherein the substituted phenyl or phenoxy is independently substitutedby one or more substituents selected from: halogen, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl, andtrifluoromethoxy; R₂ is H, phenyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, orunsubstituted or substituted amino, wherein the substituted amino groupis substituted by one or more of the following groups: C₁-C₆ alkyl,C₃-C₇ carbocyclyl, phenyl, benzyl, aralkyl, sulfanilamino, pyridyl,C₁-C₄ acyl); unsubstituted or substituted C₃-C₆ heterocycloalkylcontaining one or two oxygen or nitrogen, and unsubstituted orsubstituted phenoxy, wherein the substituted groups are independentlysubstituted by one or more of the following groups: halogen, C₁-C₆haloalkyl, amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy, and benzyl; R₃ is H, C₁-C₈ alkoxyl, halogen, mercapto,cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C₁-C₆straight-chain or branched-chain alkyl, phenyl, aralkyl, thioureido, orunsubstituted or substituted amino, wherein the substituted amino groupis substituted by one or more of the following groups: C₁-C₆straight-chain or branched-chain alkyl, C₃-C₆ heterocycloalkyl, phenyl,aralkyl, sulfanilamino, pyridyl, and C₁-C₄ acyl; R₄ is H, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, mercapto,hydroxyl, trifluoromethyl, trifluoromethoxy, or unsubstituted orsubstituted phenoxy, wherein the substituted phenoxy is substituted byone or more of the following groups: halogen, C₁-C₆ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₅ is H,C₁-C₆ straight-chain or branched-chain alkyl, or unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₆ haloalkyl, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto,cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, and unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₄ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₆ is H,C₁-C₆ straight-chain or branched-chain alkyl.
 7. The process of claim 6,wherein the polar solvent does not change under the reaction conditionsand is selected from the group consisting of: 1,2-dimethoxyethane, THF,DMF, dichloromethane, acetone, EA, methanol, ethanol, water, or mixedsolvent thereof, preferably selected from THF, water, methanol or themixture thereof.
 8. The process of claim 6, wherein the reactiontemperature is between 70° C. to 90° C.
 9. The process of claim 6,wherein the reaction time is 15 minutes to 2 days, preferably 30 minutesto 1 day.
 10. A process for preparing a compound of Structural FormulaII, or pharmaceutically acceptable salts, solvates, or hydrates thereof,which comprises the step of: treating compound (Ia), in the presence ofcesium carbonate, with compound (IIa) in a polar solvent at atemperature of about 60° C. to about 100° C., to form compound (II) tocause the reaction (2):

wherein: R₁ is a hydro, or C₁-C₆ alkyl, C₁-C₈ alkoxyl, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, phenoxy,unsubstituted C₃-C₆ heterocycloalkyl or substituted C₃-C₆heterocycloalkyl, wherein the substituted C₃-C₆ heterocycloalkyl issubstituted by one or more of the following groups: C₁-C₈ alkyl,halogen, C₃-C₆ cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, C₁-C₆haloalkyl, amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy; unsubstituted or substituted C₆-C₁₂ heteroarylcontaining one or two oxygen or nitrogen, unsubstituted or substitutedC₃-C₆ heterocycloalkyl containing one or two oxygen or nitrogen,unsubstituted or substituted (C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkylcontaining one or two oxygen or nitrogen, unsubstituted or substitutedphenyl, unsubstituted or substituted (C₅-C₁₂)aryl(C₁-C₆)alkyl (such as:benzyl, phenethyl, naphthalen-1-ylmethyl), unsubstituted or substitutedphenoxy, unsubstituted or substituted carbobenzoxy, wherein thesubstituted groups are independently substituted by one or more of thefollowing groups: halogen, oxo, C₁-C₆ alkyl, C₁-C₈ alkoxyl, C₁-C₆haloalkyl, amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy; unsubstituted or substituted phenyl or phenoxy,wherein the substituted phenyl or phenoxy is independently substitutedby one or more substituents selected from: halogen, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl, ortrifluoromethoxy; R₂ is H, phenyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy,unsubstituted or substituted amino wherein the substituted amino groupis substituted by one or more of the following groups: C₁-C₆ alkyl,C₃-C₇ carbocyclyl, phenyl, benzyl, aralkyl, sulfanilamino, pyridyl,C₁-C₄ acyl); unsubstituted or substituted C₃-C₆ heterocycloalkylcontaining one or two oxygen or nitrogen, or unsubstituted orsubstituted phenoxy, wherein the substituted groups are independentlysubstituted by one or more of the following groups: halogen, C₁-C₆haloalkyl, amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy, or benzyl; R₃ is H, C₁-C₈ alkoxyl, halogen, mercapto,cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C₁-C₆straight-chain or branched-chain alkyl, phenyl, aralkyl, thioureido,unsubstituted or substituted amino, wherein the substituted amino groupis substituted by one or more of the following groups: C₁-C₆straight-chain or branched-chain alkyl, C₃-C₆ heterocycloalkyl, phenyl,aralkyl, sulfanilamino, pyridyl, and C₁-C₄ acyl; R₄ is H, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, mercapto,hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted phenoxy, wherein the substituted phenoxy is substituted byone or more of the following groups: halogen, C₁-C₆ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₅ is H,C₁-C₆ straight-chain or branched-chain alkyl, unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₆ haloalkyl, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto,cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₄ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy R₆ is H, C₁-C₆straight-chain or branched-chain alkyl; and R₇ are each, independently,H, C₁-C₆ straight-chain or branched-chain alkyl, halo, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl, ortrifluoromethoxy.
 11. The process of claim 10, wherein when R₄ is H, theprocess comprises the steps of: a) synthesizing α-substitutedphenylpropionate ester using the reaction (3):

b) preparing substituted or unsubstituted pyridine using condensationreaction (4):

or, when R₂ is substituted amino, R₃ is H, and R₁₆ is as defined inStructural Formula V using reaction (5):

c) preparing 4-(pyrimidinyl-oxy)-phenylpropionate ester using reaction(6):

wherein all the substitutes in the reaction are defined for StructuralFormulas above beside R₄.
 12. The process of claim 10, wherein when R₄is methyl, the process comprises the steps of: a) preparing theα,α-substituted phenylpropionate ester using the reaction (7):

b) preparing substituted or unsubstituted pyridine using condensationreaction (8):

or, when R₂ is substituted amino, R₃ is H, and R₁₆ is as defined inStructural Formula V using reaction (9):

c) preparing 4-(pyrimidinyl-oxy)-phenylpropionate ester using reaction(10):

wherein all the substitutes in the reaction are defined for StructuralFormulas above.
 13. A pharmaceutical composition comprising: (i) atleast one compound selected from the compounds of Structural Formula I,or the pharmaceutically acceptable salts, solvates, or hydrates thereof,

wherein: X is CH₂, CH(OH), C(O)O, NH, S, or SO₂; Y is an unsubstitutedor substituted phenyl, wherein the substituted phenyl is substituted byone or more of the following groups: C₁-C₆ straight-chain orbranched-chain alkyl, halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, and trifluoromethoxy; n is 0, 2, 3, or4; R₁ is a hydro, or C₁-C₆ alkyl, C₁-C₈ alkoxyl, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, phenoxy, unsubstitutedC₃-C₆ heterocycloalkyl or substituted C₃-C₆ heterocycloalkyl, whereinthe substituted C₃-C₆ heterocycloalkyl is substituted by one or more ofthe following groups: C₁-C₈ alkyl, halogen, C₃-C₆ cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy; unsubstituted orsubstituted C₆-C₁₂ heteroaryl containing one or two oxygen or nitrogen,unsubstituted or substituted C₃-C₆ heterocycloalkyl containing one ortwo oxygen or nitrogen, unsubstituted or substituted(C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing one or two oxygen ornitrogen, unsubstituted or substituted phenyl, unsubstituted orsubstituted (C₅-C₁₂)aryl(C₁-C₆)alkyl (such as: benzyl, phenethyl,naphthalen-1-ylmethyl), unsubstituted or substituted phenoxy, andunsubstituted or substituted carbobenzoxy, wherein the substitutedgroups are independently substituted by one or more of the followinggroups: halogen, oxo, C₁-C₆ alkyl, C₁-C₈ alkoxyl, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy; and unsubstituted or substituted phenyl or phenoxy,wherein the substituted phenyl or phenoxy is independently substitutedby one or more substituents selected from: halogen, C₁-C₆ haloalkyl,amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl, andtrifluoromethoxy; R₂ is H, phenyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, orunsubstituted or substituted amino, wherein the substituted amino groupis substituted by one or more of the following groups: C₁-C₆ alkyl,C₃-C₇ carbocyclyl, phenyl, benzyl, aralkyl, sulfanilamino, pyridyl,C₁-C₄ acyl); unsubstituted or substituted C₃-C₆ heterocycloalkylcontaining one or two oxygen or nitrogen, and unsubstituted orsubstituted phenoxy, wherein the substituted groups are independentlysubstituted by one or more of the following groups: halogen, C₁-C₆haloalkyl, amino, mercapto, cyano, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy, and benzyl; R₃ is H, C₁-C₈ alkoxyl, halogen, mercapto,cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, C₁-C₆straight-chain or branched-chain alkyl, phenyl, aralkyl, thioureido, orunsubstituted or substituted amino, wherein the substituted amino groupis substituted by one or more of the following groups: C₁-C₆straight-chain or branched-chain alkyl, C₃-C₆ heterocycloalkyl, phenyl,aralkyl, sulfanilamino, pyridyl, and C₁-C₄ acyl; R₄ is H, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, mercapto,hydroxyl, trifluoromethyl, trifluoromethoxy, or unsubstituted orsubstituted phenoxy, wherein the substituted phenoxy is substituted byone or more of the following groups: halogen, C₁-C₆ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₅ is H,C₁-C₆ straight-chain or branched-chain alkyl, or unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₆ haloalkyl, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto,cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, and unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₄ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₆ is H,C₁-C₆ straight-chain or branched-chain alkyl; and (ii) pharmaceuticallyacceptable carrier, excipient or retarder.
 14. The pharmaceuticalcomposition of claim 13, wherein said pharmaceutical composition is inthe form of troche, capsule, powder, syrup, solution, suspending agentor aerosol.
 15. The pharmaceutical composition of claim 13, wherein saidpharmaceutical composition is formulated in unit dose form.
 16. Thepharmaceutical composition of claim 13, wherein the amount of component(i) is in the range from 0.05 to 500 mg, preferably 0.5 to 200 mg, andmore preferably 0.1 to 100 mg.
 17. The pharmaceutical composition ofclaim 13, wherein the amount of component (i) is 0.001-99.9 weightpercent, preferably 0.01-99 weight percent, and more preferably 0.1-90weight percent, based on the total weight of the pharmaceuticalcomposition.
 18. The pharmaceutical composition of claim 13 furthercomprising one or more other medicine in the treatment and prevention ofpolycystic kidney and cancer, preferably selected from ACE inhibitor andPPAR-γ agonist, more preferably selected from Enalapril, Benazepril, andRosiglitazone. 19-24. (canceled)
 25. A method for the treatment of thesubject suffering from polycystic kidney and/or cancer comprisingadministrating an effective amount of at least one compound selectedfrom the compounds of Structural Formula I, or the pharmaceuticallyacceptable salts, solvates, or hydrates thereof to the subject in needof such treatment

wherein: X is CH₂, CH(OH), C(O)O, NH, S, or Y is an unsubstituted orsubstituted phenyl, wherein the substituted phenyl is substituted by oneor more of the following groups: C₁-C₆ straight-chain or branched-chainalkyl, halogen, C₁-C₆ haloalkyl, amino, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, and trifluoromethoxy; n is 0, 2, 3, or 4; R₁is a hydro, or C₁-C₆ alkyl, C₁-C₈ alkoxyl, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, phenoxy, unsubstitutedC₃-C₆ heterocycloalkyl or substituted C₃-C₆ heterocycloalkyl, whereinthe substituted C₃-C₆ heterocycloalkyl is substituted by one or more ofthe following groups: C₁-C₈ alkyl, halogen, C₃-C₆ cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, C₁-C₆ haloalkyl, amino, mercapto, cyano,nitro, hydroxyl, trifluoromethyl, trifluoromethoxy; unsubstituted orsubstituted C₆-C₁₂ heteroaryl containing one or two oxygen or nitrogen,unsubstituted or substituted C₃-C₆ heterocycloalkyl containing one ortwo oxygen or nitrogen, unsubstituted or substituted(C₆-C₁₂)heterocycloalkyl(C₁-C₆)alkyl containing one or two oxygen ornitrogen, unsubstituted or substituted phenyl, unsubstituted orsubstituted (C₅-C₁₂)aryl(C₁-C₆)alkyl (such as: benzyl, phenethyl,naphthalen-1-ylmethyl), unsubstituted or substituted phenoxy, andunsubstituted or substituted carbobenzoxy, wherein the subtituted groupsare independently substituted by one or more of the following groups:halogen, oxo, C₁-C₆ alkyl, C₁-C₈ alkoxyl, C₁-C₆ haloalkyl, amino,mercapto, cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy; andunsubstituted or substituted phenyl or phenoxy, wherein the substitutedphenyl or phenoxy is independently substituted by one or moresubstituents selected from: halogen, C₁-C₆ haloalkyl, amino, mercapto,cyano, nitro, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₂ is H,phenyl, C₁-C₆ alkyl, C₁-C₈ alkoxyl, amino, mercapto, cyano, nitro,hydroxyl, trifluoromethyl, trifluoromethoxy, or unsubstituted orsubstituted amino, wherein the substituted amino group is substituted byone or more of the following groups: C₁-C₆ alkyl, C₃-C₇ carbocyclyl,phenyl, benzyl, aralkyl, sulfanilamino, pyridyl, C₁-C₄ acyl);unsubstituted or substituted C₃-C₆ heterocycloalkyl containing one ortwo oxygen or nitrogen, and unsubstituted or substituted phenoxy,wherein the subtituted groups are independently substituted by one ormore of the following groups: halogen, C₁-C₆ haloalkyl, amino, mercapto,cyano, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, and benzyl;R₃ is H, C₁-C₈ alkoxyl, halogen, mercapto, cyano, nitro, hydroxyl,trifluoromethyl, trifluoromethoxy, C₁-C₆ straight-chain orbranched-chain alkyl, phenyl, aralkyl, thioureido, or unsubstituted orsubstituted amino, wherein the substituted amino group is substituted byone or more of the following groups: C₁-C₆ straight-chain orbranched-chain alkyl, C₃-C₆ heterocycloalkyl, phenyl, aralkyl,sulfanilamino, pyridyl, and C₁-C₄ acyl; R₄ is H, C₁-C₆ straight-chain orbranched-chain alkyl, C₁-C₈ alkoxyl, mercapto, hydroxyl,trifluoromethyl, trifluoromethoxy, or unsubstituted or substitutedphenoxy, wherein the substituted phenoxy is substituted by one or moreof the following groups: halogen, C₁-C₆ haloalkyl, amino, mercapto,hydroxyl, trifluoromethyl, and trifluoromethoxy; R₅ is H, C₁-C₆straight-chain or branched-chain alkyl, or unsubstituted or substitutedphenyl, wherein the substituted phenyl group is substituted by one ormore of the following groups: halogen, C₁-C₆ haloalkyl, C₁-C₆straight-chain or branched-chain alkyl, C₁-C₈ alkoxyl, amino, mercapto,cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, and unsubstituted orsubstituted phenyl, wherein the substituted phenyl group is substitutedby one or more of the following groups: halogen, C₁-C₄ haloalkyl, amino,mercapto, hydroxyl, trifluoromethyl, and trifluoromethoxy; R₆ is H,C₁-C₆ straight-chain or branched-chain alkyl.
 26. The method of claim25, wherein said polycystic kidney is selected from autosomal recessivepolycystic kidney disease or autosomal dominant pattern polycystickidney disease; and said cancer is selected from colon, breast, lung andprostate, pituitary cancer, or leukemia. 27-28. (canceled)